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Full text of "Opening Statements Before the Committee on Appropriations"



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SUMMARY OF OPENING STATEMENT 

by 
Director, National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 



Mr. Chairman and Members of the Committee: 

Once again it is my pleasure to appear before you in con- 
nection with the Public Health Service appropriations that 
finance the program and activities of the National Institutes 
of Health. 

The present statement offers certain general considera- 
tions that relate to total activities of NIH 3 It also introduces 
separate statements on the Division of Biologies Standards, 
Division of General Medical Sciences, and central services in 
support of the Institutes' programs. 

Let me say at the outset that the additional funds made 
available to us by the Congress for 1960 have been used to good 
advantage in the conduct and support of research projects, train- 
ing programs, and research construction in the health field. 

A view of 1960 activities in broad perspective reveals that 
these programs have matured and become established and essential 
parts of the Nation's medical research effort while assuring the 
freedom and integrity of the grantees and their institutions. On 
the other hand, the needs of the institutions themselves are not 
being met. The universities, medical schools, and other centers 
for health research and teaching evince difficulty in financing 
with balance their traditional missions — research, education, and 
public service. 



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The broader our programs, the more deeply they become in- 
volved in support of the educational process. This implies an 
obligation to help the institutions sustain initiative. Grants 
enabling schools to experiment with ways of producing medical 
scientists are a step toward support of the educational process 
itself. 

The current NIH program reflects our concern over institu- 
tional strength and stability in (1) a trend toward larger grants 
for more broadly defined objectives, (2) strong fellowship and 
training programs, (3) an adjustment in the starting dates of 
training grants, (4) a proposal to provide for the full indirect 
costs of grantee research, (5) a proposal to award institutional 
research grants, and (6) development of clinical, therapeutic and 
metabolic research centers and primate colonies. 

Appraisals of NIH programs were made throughout the past 
year. These included the participation of nearly 700 nonfederal 
scientists and leaders in public affairs whose recommendations 
govern the grant and award programs; the reviews of our own research 
activities at Bethesda by distinguished consultants; and the 
responses of grantees, interested agencies, and the general pub- 
lic. There have also been several special appraisals by Federal 
groups: (1) advisors to the Senate Appropriations Committee 
assessing our current operations, (2) the General Accounting Office 
reviewing extramural programs, (3) the Appropriations Committee 
of the House of Representatives auditing certain programs and 
procedures, (4) the Office of the Surgeon General conducting 



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- 3 - 
related studies on health manpower and environmental health 
hazards, (5) the NIH task force of Dr. Kenneth M. Endicott 
studying the impact of NIH grant programs on medical schools, and 
(6) two units newly established within our Division of Fesearch 
Grants, one to facilitate program anlaysis and review, and the 
other to provide a central focus for training grants. 

The 1960 Appropriation Act contained increases of $115.8 
million over the NIH total for 1959. In our apportionment 
request, which was approved by the Bureau of the Budget, we pro- 
jected an unexpended balance of $5.85 million. As of this date, 
this would appear to be a relatively accurate estimate. It is 
possible, however, that when the February /March Council meetings 
are completed, this estimate may change. 

Ten substantive highlights of the 1960 NIH program may be 
cited. Advances were made in (1) collaborative studies of peri- 
natal disease, (2) the cancer chemotherapy program, (3) collabora- 
tive studies in psychopharmacology, (4) the field of viruses and 
cancer, (5) the development of a program in mathematics and 
physical biology, (6) activities concerning the development of a 
live-virus polio vaccine, (7) new construction at Bethesda, (8) 
programs to support research in other countries and exchange of 
scientists and scientific information, (9) the establishment of 
programs for training in basic sciences, and (1) the program of 
grants to assist in the construction of health research facilities „ 

Thus far in 1960, research grant applications have been re- 
viewed in unprecedented number — 7,975. But an increase in the num- 
ber of Study Sections to 33 has enabled us to keep pace. 



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Special review procedures have been established in compliance 
with the President's criteria seeking to help avoid the hazards 
of rapid program growth. Some 64 grant applications approved 
in June were denied support when reexamined in October. But 
the volume of new applications has continued to rise, and the total 
number recommended for approval has not decreased. High standards 
of review have been maintained despite the rapid increase in ap- 
propriations . 

The individual witnesses will introduce detailed state- 
ments of research and program highlights related to NIH appropria- 
tions for 1959. 

In the President's 1961 budget request, the proposed NIH 
appropriations total $426.7 million. Included is a $5 million 
reduction below the authorized $30 million under the Health 
Research Facilities Construction Act. The Department, however, is 
considering legislation that would make similar matching grants 
available for construction of facilities not only for research 
but also for teaching. Also included in our budget request are 
increases in funds for research and for development of certain 
animal facilities. 

Forces that may be expected to shape future trends in NIH 
programs include (1) greater attention to the development of 
research resources and to mechanisms permitting more stability 
in research careers, (2) modifications in research support which 
will strengthen the institutions as such, (3) decentralization of 
some processes for determining the support of research and training, 
and (4) application of new techniques and disciplines, enabling 
research to probe deeper into the unknown. 



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OPENING STATEMENT 
by 
Director, National Institutes of Health 
COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 



Mr. Chairman and Members of the Committee: 

Once again it is my pleasure to appear before you in connection 
with the Public Health Service appropriations that finance the programs 
and activities of the National Institutes of Health. 

A familiar face is missing from our group of witnesses, Mr. Chairman. 
I refer to Dr. C. J. Van Slyke, who retired from the Public Health Service 
last December after nearly thirty years of dedicated service to medicine 
and public health. During the last half of his career, Dr. Van Slyke was 
the primary architect and builder of the research, training, and 
construction grants through which the Institutes now support a large 
part of the Nation's total medical research effort. Our grant and 
awards programs reflect Dr. Van's basic conviction that Federal funds 
can be provided under terms that permit the individual freedom of 
inquiry, that support institutions in the achievement of their own goals, 
and that at the same time focus in a very direct sense on the immediate 
health needs of the American people. I know the Committee will miss 
having him here, as we do. 

Dr. Van Slyke 1 s work is now being carried out by Dr. Kenneth M. 
Endicott, who is here today. Dr. Endicott has had a series of increas- 
ingly responsible positions at NIH, including that of laboratory scientist 
in chemistry and pharmacology, Scientific Director of the Division of 






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Research Grants, Director of the Cancer Chemotherapy Program from 
its inception until it became an established and unified research 
activity, and most recently Associate Director of NIH with special 
emphasis on our training grants and awards. 

It is my purpose to place before you certain general considerations 
that relate to the total activities of the National Institutes of Health. 
It is also my purpose to provide the Committee with more specific 
information concerning the two programs- -the Division of General Medical 
Sciences and the Division of Biologies Standards- -that are financed under 
the appropriation entitled "General Research and Services, NIH,'" as well 
as our activities under a management fund through which certain services 
are provided centrally in support of all of the Institutes and operating 
programs. I have with me prepared statements on each of these three 
topics. I shall be glad to submit them for the record at the conclusion 
of my general remarks, or to handle them in whatever other way the 
Committee may wish. 

Let me say at the outset that the additional funds made available 
to us by the Congress for i960 have been used to good advantage in the 
support of projects of high quality. Scientists, scientific institutions, 
and the people as a whole have reason to be grateful for the part played 
by the Congress in supporting medical research as a sound investment in 
America's future. It is our primary role at NIH to serve as custodians 
of these funds derived from taxes, appropriated by the Congress, and used 



to conduct and support current research; research; academic, and service 
training, and research construction in the health field. This is not a 
passive role: we find it creative and challenging and most rewarding, 
and like the scientists and scientific institutions supported under 
our grants and awards programs, we too have good reason to acknowledge 
this Committee's interest and affirmative action on medical research 
matters that have such an intimate relationship to the Nation's health. 

PERSPECTIVE ON i960 ACTIVITIES 
i960 has been a year in which the strengths and limitations of 
our medical research support processes have stood out in sharp focus. 

The strengths are derived from the increasing maturation of 
programs that at their inception were sound in principle and have now 
Decome established and essential parts of the Nation's medical research 
effort. These programs began with our own traditional research activity 
in Bethesda, to which breadth and depth were added as new Institutes and 
new facilities were brought into being. Grant support of the research 
projects of nonfederal scientists was initiated in 19^6. Programs to 
develop manpower and facilities resources followed thereafter. Elabora- 
tions and refinements of our support mechanisms have been accompanied by 
rapid increases in annual appropriations for these purposes. Today, our 
programs support more than one -third of all medical research in this 
country. Thousands of young men and women are being aided while they 



complete their postgraduate training for research, academic, and 

service careers. And hundreds of research laboratories are being constructed 

or renovated, in part with matching grants from our appropriations. 

In essence, those aspects of our programs that provide current 
support for individual research projects and assistance to talented 
individuals during their advanced training- -programs which together 
represent more than 85 percent of our I960 activities- -pose no major 
problems of either a policy or an operating nature. There will of 
course continue to be questions to be answered and adjustments to be 
made as to the level, direction, and emphasis in these established pro- 
grams. But the primary task, that of developing effective means for 
Federal funds to share in the support of individual research projects 
and postgraduate training while at the same time assuring the freedom 
and integrity of the grantees and their institutions, is behind us. 

It is my belief, at this point in time, that these established 
and accepted activities in support of the individual should continue 
to be the central focus of our programs. 

NEEDS OF GRANTEE INSTITUTIONS 
On the other hand, there is abundant evidence today that although 
many of the specific needs of the individual and of the individual fields 
of science are being met, the needs of the grantee institutions are not 
being met. The universities, medical schools, and other centers for 



5 - 



research and teaching in the health sciences serve the people in three ways: 
in research, in education, and in public service. Their institutional needs 
are overwhelming, and the means for satisfaction of those needs are 
inadequate . 

The point may be made that if the Nation's system of educational 
and research institutions were financially capable of doing so, they 
c ould : 

1. Provide a stable background for current activities supported 
by outside funds. 

2. Extend research to include opportunities newly apparent to the 
medical investigator --ranging from the active entrance of 
university sciences (such as mathematics, chemistry, and physics 
on the one hand and genetics, developmental and systematic 
biology, andosocial anthropology on the other) to the 
development of modern epidemiology in the design of studies of 

a demographic nature as an essential area of proper study in 
the causation of chronic illness. 

3- Provide an organizational structure for the grouping of diverse 
disciplines and approaches centered about broad disease 
categories, without at the same time distorting the fundamental 
structure and function of the institutions of higher learning. 

The inability of our system as a whole to do any of these things 
adequately and in a balanced fashion is clear. This gives rise to concern 
about the financial capacity of our academic institutions as they look 
to the challenges before them and the Nation. 

As NIH programs are broadened to encompass activities such as 
extensive training programs, they inevitably affect the educational 
process. This is also true when support of research is broadened, 



as it has been, to the point where the whole institution is involved. 

NIH programs not only influence the educational process, but also directly 

support part of it. 

The Congress, and all others who present, support, or act upon our 
appropriation requests, should understand fully that the broader our 
programs are, the more deeply they become inevitably involved in support 
of the educational process. This direct involvement places upon the NIH 
the obligation to help the institutions sustain the initiative to develop 
their own objectives. This has been done through grants enabling schools 
to experiment with ways of producing medical scientists. More will be 
done along this line as NIH activities continue to extend beyond support 
of research and training to support of segments of the educational 
process itself. 

Finally, in presenting our programs to the Congress, we will 
present proposals for improving the mechanisms, and the terms and conditions, 
through which support for research and training is provided. The ways 
in which funds are made available affect the productivity of investigators, 
and are therefore as important as the dollar level of support and the kind 
of research which is aided. 

For an activity such as ours, with focus on support of the 
research component of nonfederal institutions, there is an obligation 
to provide such support under terms and conditions which recognize 
and seek to ameliorate the institutions' dilemma, or at the very least 



do not increase their already pressing problems. 

There are a number of vays in which the i960 NIH program and the 
1961 proposal reflect our concern over institutional strength and 
stability. 

1. The research project grants, without deviation from standards 
of excellence, continue to follow a trend towar d larger grants f or more 
broadly defined objectives , with support committed for longer periods 

of time. This trend is the product of the changing nature of scientific 
endeavor and the significant increase in the funds available, but it has 
positive value to the stability of the institutions where the research is 
carried. out. 

2 . The fellowshi p and training grants and a wards programs , extend- 
ing into new fields and utilizing new mechanisms during a period of rapid 
expansion, have contributed in a very direct sense to the total strength 
of grantee institutions. Our programs are centered on increasing the 
number and quality of manpower; but both the teaching and the public 
service aspects of the schools are enhanced by NIH support both of 
individuals in training and of broader support of training programs at 
undergraduate and postgraduate levels. 

3. A start has been made toward assisting the schools in the 
provision of programs of excellence by making it possible for them to 
plan the selection of faculty and the recruitment of talented students 

well in advance of the start of the academic year. By adjusting the starting 



dates of training grant s so that commitments are made in June for the 
ensuing fiscal year, the program itself is greatly improved and at the 
same time the institution is strengthened. A total of $8 million of the 
i960 training grant increase was used for this purpose , changing the 
starting date on roughly one -third of the graduate training grants in 
this field. 

k. We continue to endorse the principle that granting agencies 
should provide f or the full indirect costs (overhead) of r esearch that 
is grant -supported . This is a primary concern both of grantee institutions 
and of the Executive Branch. Practices now vary among Federal granting 
agencies, but as a result of study, steps toward establishment of a 
uniform indirect cost policy have been taken. In the meantime, since our 
indirect cost practice is more restrictive than that of any other 
Federal agency, it is again proposed that we lift the 15 percent restriction 
that now obtains and permit payments up to an average of 25 percent, 
starting with grants approved for payment after January 1, 1961. 

5. The Administration has recently transmitted to the Congress 
our legislative proposal to provid e research grants that are institutional 
in nature instead of being defined in terms of a specific project. Under 
this proposal, based on a formula which relates the size of the 
institutional grant to the level of research activity of the institution, 
up to 15 percent of the total funds available for NIH research grants 
would eventually be apportioned among the institutions that contain 



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these activities. This money would continue to be earmarked for 
research, but its specific use would be discretionary with the 
institution- -for establishing new research programs, adding research 
resources, paying salaries, and hopefully establishing new career 
opportunities for fulltime research personnel, and so on. This program 
should not be interpreted to be one aimed primarily toward aiding 
institutions. Rather, in meeting emerging research needs as they perceive 
them, it would be a long forward step toward strengthening an 
environment as a whole via grant support of its research function. It 
stems from a strong conviction that a broadly based medical research 
program for the Nation must continue to provide for peripheral decisions 
of a substantive nature as a balance to those made centrally. It seems 
quite likely, as an important indirect benefit, there would occur direct 
strengthening of the institutions concerned. If the institutional research 
grant legislation is enacted, we would propose to limit such support 
initially to schools of medicine, dentistry, and public health, and to 
start the program with 5 percent of the annual research grant appropriation. 

6. A final aspect of current NIH activity bearing on institutional 
strength and stability is found in the new grant programs for the devel- 
opment of two kinds of research resources: therap eutic and metabolic 
research c enters, a nd primate colonies . The Congress made available in 
NIH i960 appropriations $3 million and $2 million respectively for these 
purposes. They require different approaches from any programs in which 



10 



NIH has thus far engaged. In the clinical research units, we are support- 
ing the development of specialized resources for controlled clinical 
study within a single institution. The support includes renovation, 
equipment, salaries, and operating costs. In the case of primate 
colonies, we are asking selected institutions to develop for regional 
use resources which will assure the ready availability of these 
experimental animals for qualified institutions and investigators. The 
regional nature of such resources has made it advisable to provide funds 
for construction on a non-matching basis. The definitions and modus 
operandi for both of these new programs have been worked out with extreme 
care by NIH staff and outside advisors. The response of the medical 
schools and universities has been gratifying, and a number of applications 
from qualified institutions have been received and are under review by 
the appropriate advisory bodies. The presence of these two programs in 
our present activity warrants special comment because they represent 
a new approach to the support of research—an approach that is directed to 
general rather than specific progress in research, to institutional 
stability, and to the development of resources to permit full use to 
be made of the investigators' talents. 

APPRAISALS OF NIH PROGRAMS 
Inherent in the rapid growth and change of NIH programs is 
the requirement they be both periodically and continuously appraised by 
internal and external groups. 



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The fundamental appraisal, of course, is that carried out 
in the normal course of program execution. The nearly 700 nonfederal 
scientists and leaders in public affairs who review and recommend 
definitive action on our extramural programs, the distinguished 
consultants who review our own research activities in Bethesda, 
and indeed the many thousands of individuals receiving grants or 
administering institutions in which grant -supported work is carried 
out—these constitute a built-in appraisal mechanism providing a 
continuous flow of knowledge as to the strengths and limitations of 
our programs. In addition, the public interest and that of interested 
groups, such as foundations, industry, and voluntary health agencies, 
lead to assessments of performance from varied points of view. 

From within the Federal establishment itself, there have been 
a number of appraisals of special interest. 

1. Under a resolution of the Senate Appropriations Committee, 
a special group of advisors was called together to assess NIH's 
current operations and to advise the Senate Committee as to their 
probable trends and directions. These consultants, chaired by 
Mr. Boisfeuillet Jones of Emory University, have spent a great deal 
of time with the NIH staff and with others interested in our programs. 
Their report will be made to the Senate this spring; for our part, 
however, we have found it stimulating and helpful to have this kind of 
opportunity to discuss and sometimes to defend what we do. 



12 



2. A second study of NIH extramural programs was completed 
in November by the General Accounting Office as part of a larger study of all 
NIH activities. Their report, transmitted to the Congress together with 
my comments on their recommendations, contains four or five procedural 
suggestions that will be helpful in maintaining better control over a 
program whose rapid expansion makes these measures necessary and desirable. 
Our staff has worked closely with the GAO subsequent to the preparation 
of its recommendations. We believe that the study was conducted with 
excellent insight into our operational policies and represents a 
well-balanced appraisal of our activities. Its recommendations appear 
sound. Several of these we had already initiated or determined for 
ourselves to undertake prior to completion of their report, and adjustments 
to meet the remainder are now in progress. We look upon this and all 
other outside assessments of our activities as constructive and helpful, 
and were grateful to the GAO auditors for pointing out ways to improve our 
mechanisms for research support. 

3- The Appropriations Committee of the House of Representatives 
asked its staff to audit certain of the NIH programs and procedures. We 
have not seen their report, but we found the views and line of question- 
ing taken by this group to be very helpful and look forward to a 
constructive report from the group. 



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h. Although not directed to NIH programs specifically, studies 
such as those carried out by the Office of the Surgeon General on the 
supply of physicians and other health personnel, and on the increasing 
significance of environmental hazards to the public health, were 
valuable to us for program planning purposes. 

5. Within our own establishment, a Task Force headed by 

Dr. Kenneth M. Endicott made an intensive study of the impact of NIH 
grant programs on twenty representative medical schools. The published 
report, in which the Association of American Medical Colleges cooperated, 
contained much of value both to us and to the schools. More recently, 
Dr. Endicott has conducted a two-part study of NIH training programs. 
The first part consisted of an assessment of the information that can 
be gained from our own records, supplemented by a selective questionnaire 
The second part was extended visits to selected schools to discuss and 
evaluate their performance with training grant funds from NIH. There 
has not yet been time for the results of this Study to be summarized 
and evaluated; however, it is clear that it will be most helpful in 
giving us additional insight into this rapidly growing segment of 
our total program. 

6. The need for improved information and surveillance as a 
basis for informed administrative decisions has led to the establishment 
within our Division of Research Grants of two units: one group to 
maintain a continuous record of NIH support activities for the purpose 



- Ik 



of analysis and review , and a second group to provide in DRG the kind 

of central activity for training grants that the Division now provides 

for research grants. Such organizational arrangements are in the 

process of being brought into balance by modifications of our administrative 

structure within the Institutes and the immediate Office of the Director, NIK. 

Steps are now being taken to provide senior staff assistance with special 

competence to give leadership to present extramural programs and to 

advise on emerging policies and problems in this field. 

The above items are but a sample of the appraisal process as 
applied to NIH programs. There are many other instances that could be 
cited, at all levels. The essential point to convey is that in a support 
role such as ours, where performance is geared in large measure to the 
interests and capacities of others to do a job, the processes for 
assessing each proposed step before actually defining and undertaking 
it are of the utmost importance. 

I960 PROGRAM PERFORMANCE 
Perhaps the best background against which to measure NIH's i960 
performance is found in the apportionment request submitted to and 
approved by the Bureau of the Budget following the President's signature 
of the Labor-HEW i960 appropriation act. The Budget provided funds and 
indicated goals; the apportionment document outlined a philosophy of 
operation and a plan of attack. 



15 



The bill contained increases of $115.8 million over the 
1959 obligations for the nine appropriations administered by the NIH. 
The bulk of this increase ($95 «6 million) was for grant -supported 
activities; the balance was primarily for chemotherapy contracts 
($6.9 million) and direct research activities ($5 million). 

Our estimate at the time of the apportionment request was that 
•I&.5 million might remain unexpended in research grant s, $1 million 
in chemotherapy contracts, and lesser amounts in direct operations. 
In retrospect, with the year more than half past, it appears to have been 
a good estimate. 

The i960 apportionment plan, including our $5. 9 million estimate 
of unprogrammed reserve, was transmitted by the Department to the Bureau 
of the Budget on August 26 and approved by the Bureau, as submitted, 
on September 12, 1959 • The Bureau asked for a reappraisal by 
December 1, 1959. Our response on November 25, 1959, essentially confirmed 
the original apportionment estimates, although indicated the possibility 
of slightly greater needs in some programs. 

Among the substantive highlights of the NIH's i960 programs-- 
highlights which will be emphasized in the testimony of the Institute 
Directors--I have selected ten for brief mention here. 

1. The collaborative studies of perinatal disease by the 
National Institute of Neurological Diseases and Blindness are now well 
established, the cooperating institutions are moving ahead and preliminary 



16 - 



data are beginning to flow from the participants. This long-term 
undertaking, seeking new knowledge about mental retardation, cerebral 
palsy, and other conditions, exemplifies the values NIH programs can 
have when there is need for central planning, stimulation, and coordination 
in a field of scientific endeavor, but also the difficult problems posed 
by the need for central determination of plans and details of operation; 
greater comprehension by the individual participants of their role in 
the general plan; a great deal in the way of central supportive and 
analytical services; and more broadly conceived informational functions. 

2. The program of cancer chemotherapy, benefiting greatly from a 
process of critical self-evaluation at this stage in its development, 
continues to pursue the known paths and to seek new avenues that will 
permit exhaustive exploration of the possibility that chemical agents 
useful in the treatment of cancer may be found. 

3. Another collaborative program is found in the National 
Institute of Mental Health's studies in the field of psychopharmacology. 

At a i960 level of more than $6.5 million, this program includes evaluation 
of the clinical efficacy of drugs that are potentially useful in the 
treatment of psychiatric conditions, the development and assessment of 
ways to identify and characterize new drugs at the preclinical level, and 
studies of the basic mechanism of action of known psycho-active drugs. In 



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this program, too, the central functions of the Institute in support 
of this essentially research grant activity are of great significance 
to the continuing productivity of the program. 

k. In the promising field of viruses and cancer a distinguished 
group of virologists is now receiving sizeable, long-term support. 
This is not a collaborative study in the sense that the perinatal 
studies are. But the competence and relationships of these scientists, 
and their informal agreement to explore different aspects of the field, 
promises swift and imaginative exploration of the viral aspects of 
cancer causation. 

5. In part as a result of NIH interest, stimulation, and support, 
considerable progress has been made toward the effective application 

of the knowledge and techniques of mathematics and the physical sciences 
to the solution of biological problems. 

6. In the execution of its regulatory function, which for 
biological products must be based on a solid research foundation, 
the Division of Biologies Standards has given both leadership and 
restraint to the development of a possible live virus vaccine against 
poliomyelitis- -leadership to ensure that there is sound exploration 
of all scientific aspects related to this experimental product, and 
restraint so that all necessary assurances are obtained before it can 
become available for general use. 



- lb 



7. Progress on the four major structures at Bethesda now 
being built to broaden NIH intramural programs continues to be 
satisfactory. The new building to house the Division of Biologies 
Standards is nearly complete and will be occupied this year. The 
National Institute of Dental Research Building has its major structural 
work completed. The addition to the surgical facilities of the 
Clinical Center is progressing well. And the excavation has been made 
for our badly-needed office facility. These four facilities, representing 
a capital investment of some $18 million, will further establish NIH 

as one of the Nation's major resources for health research. 

8. As the substance and dimension of the NIH programs have 
grown, there has been gradually increasing support for the research 
of foreign nationals and for the interchange of scientists and 
scientific information. These activities, for all Institutes, 
reached a level of $8 million in i960, as contrasted with $5 million 
in 1959« These "international" activities of NIH are in fact 
National in objective and operation; the activities are supported to 
carry out statutory missions, recognizing that attainment of the medical 
research objectives of the U. S. requires cooperation with or support 

of research in other countries and two-way exchange of scientists. In 

this connection, it should be pointed out that NIH is itself becoming 

an increasing focus for visits to this country by scientists from abroad. 



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9« In the Division of General Medical Sciences, significant 
progress has been made in the establishment of productive training 
programs leading to the availability of greater numbers of people 
trained in such basic disciplines as pharmacology, biochemistry,, 
epidemiology, and genetics. 

10, In the program of grants to assist in the construction of 
health research facilities, now in its fourth year, the Council has 
reviewed approximately $65 million in grant applications. The program 
continues to meet an important need of the schools . The inability of 
certain institutions to raise matching funds continues to be a matter 
of concern. 

Thus far in i960, Mr. Chairman, in the research grants field, 
some 7;975 competing applications have been reviewed. This compares 
with 5,833 in 1958 and 2,750 in 1956. During that four-year span, 
however, the number of Study Sections has increased from 21 to 33 and 
the average number of days per meeting from 1.8 to 2.6. Thus each 
Study Section is reviewing only an average of 31 applications per 
meeting day--fewer than six more than was true in 1956, and providing 
one indication that it has been possible to maintain high review standards 
during a period of rapid growth. 

With the signing of the i960 Labor-HEW appropriation act, the 
President developed a series of conditions to govern the expenditure 
of NIH grant funds to help assure that certain potential hazards of rapid 



20 - 



growth could be avoided. Such conditions, superimposed on normal 
review procedures developed with excellence in mind, are difficult 
of assessment in terras of their specific impact on programs. During i960, 
a recent trend toward a decline in the approval rate on new grant 
applications continued. Under special review procedures established 
in compliance with the President's criteria, some 6k applications 
approved with lowest priorities in June were denied support when 
re-examined in October. At the same time, the volume of new grant 
applications has continued to increase, and there has been no evident 
decrease in the total volume of requests recommended for approval. An 
examination of all of the objective evidence bearing on the qualitative 
aspects of the research grants program suggests that it has been possible 
to maintain high standards of review despite the rapid increase in 
appropriations for the support of research. 

The number of items that should be singled out for special 
treatment in a general statement on NIH programs is almost without limit. 
I have chosen to list a few program developments for sake of illustration. 
We have prepared for the Congress, however, a detailed statement of the 
research and program highlights related to NIH appropriations for 1959* 
These will be introduced by the individual witnesses as they appear. 
In sum, they constitute an impressive record of achievement toward the 
goals set for medical research by the people who give it their support and 
by the scientists and scientific institutions who foster and carry out 
the research itself. 



21 



THE 1961 BUDGET REQUEST 

The appropriation request for NIH contained in the President's 
19ol budget request is -$^26.7 million. This compares with an estimated 

operating level of $k2k.h million in i960 an estimated operating 

level which is $5-9 million less than the i960 appropriation. 

Included is a $5 million reduction below the authorized ceiling 
of $j0 million under the Health Research Facilities Construction Act. 
As indicated in earlier testimony of the Secretary of Health, Education, 
and Welfare before this Committee, the Department is considering 
legislation to make similar matching grants available for construction 
of teaching facilities as well as research facilities in the medical and 
related schools. If such legislation is enacted, the funds to be requested 
would exceed the 05 million reduction in the Research Facilities 
Construction program. 

Also included is an increase in the availability of funds for 
research, under a policy decision that within the ceiling authorized 
an increase for this purpose should have priority over other aspects 
of our total program. 

Included in the consolidated appropriation request, "Buildings and 
Facilities, Public Health Service," are three items seeking obligational 
authority for NIH construction. An item of $1,150,000 is requested for 
cage-washing equipment, cages, and alterations to our small animal 
breeding facility, Wings F and G. This space has been in use for offices 



- 22 - 

pending completion of the new office building, and the funds are needed 
to restore the space for its intended purpose. The other two items are 
$350,000 to plan and construct an animal research facility needed at our 
Drug Addiction Center at Lexington, Kentucky, and $250,000 for necessary 
steps toward the development and use of the farm site acquired in 
i960- -permanent animal buildings, temporary bleeding stalls, records 
storage, and other minor structures, as well as completion of a master 
site plan. 

In sum, the budget request for I96I calls for a period of 
consolidation of the gains achieved in i960, with a modest increase in 
the support of research obtained through the implementation of decisions 
indicated above. 

As one looks ahead, it is apparent that the future evolution 
of NIH programs will be shaped by forces such as these: 

1. Greater attention will be paid to the development of research 
resources and to mechanisms which will permit greater stability in 
research careers. 

2. Mechanisms for the support of current research will be 
modified so that support of research in schools and other research 
institutions will strengthen the institutions as such, as well as the 
research function it contains, so that they can assume greater control 
over their own destinies as well as their discrete research activities. 



23 



3. An increasing number of the decision-making processes which 
determine the support of individual scientists in research and in 
training for research will be decentralized to the local level. 

h. Changes in the levels and mechanisms of support for medical 
research will be accompanied by changes in scope and depth of penetration, 
so that by using new techniques and embracing new disciplines, medical 
research will be able to probe ever deeper into the unknown. 

The dominant theme among those who study and report on the 
present medical scene is the need for a broad and reliable financial 
underpinning for the institutions of higher learning. Although research 
programs can be designed to avoid placing further stress on the 
institutions, they cannot meet their total needs. Ultimately, the present 
schools must be materially strengthened and new schools created if the 
Nation is to meet its obligations in a responsible fashion. 

Some steps toward the achievement of these long-range goals are 
reflected in the Administration's fiscal and legislative proposal for 
196l : institutional research grants; initiation of increased overhead 
on research grants; continuation of programs initiated in i960 to develop 
research resources; continued broadening of NIH research grant programs; 
and other activities designed to strengthen and return control to the 
grantee institutions. 



2k 



I am grateful to the Committee for its support and understanding 
of the issues faced in this and former years during the development of 
NIH programs. We will do our utmost in the administration of these 
programs to demonstrate that your confidence is not misplaced. 



ATTACHMENT A 
DIVISION OF BIOLOGICS STANDARDS 
BACKGROUND 

The Federal Government's responsibility for the control of bio- 
logical products began on July 1, 1902, with the passage by the Congress 
of an Act to regulate the sale in interstate commerce of all viruses, 
serums, toxins, and analogous products applicable to the prevention and 
cure of diseases of man. The statute, now a part of the Public Health 
Service Act, is basically the same as in 1902 when the technical respon- 
sibilities of the biologies program were assigned to the National 
Institutes of Health, then known as the Hygienic Laboratory. In 1937, 
the Laboratory of Biologies Control was created within the National 
Institutes of Health, and in 1948 it was made a part of the National 
Microbiological Institute. In June 1955, authority was granted the 
Surgeon General by the Secretary of the Department of Health, Education, 
and Welfare to expand the biologies control function of the Public 
Health Service to the status..of a separate division within the 
National Institutes of Health, called the Division of Biologies 
Standards. Its funds are derived from the appropriation "General 
Research and Services, NIH", which also finances the Division of 
General Medical Sciences. 

GENERAL MISSION 

The primary function of the Division of Biologies Standards is 
to administer the provisions of the Public Health Service Act and 
Regulations pertaining to the safety, purity, and potency of all 



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biological products offered for sale, barter or exchange in interstate 
commerce or for export or import. Such products include vaccines, 
antitoxins, therapeutic serums, and human blood and its derivatives. 

Biological materials are derived for the most part from patho- 
genic or potentially pathogenic microorganisms. The preparation of 
these materials requires careful control to minimize safety hazards 
which might occur in the course of processing. In addition to safety 
precautions, control measures are necessary to assure final products 
of satisfactory potency. Effective control requires the design and 
development of adequate and practical standards for production and 
testing, careful surveillance of production methods, and the continuous 
improvement of testing procedures. 

The introduction in the early 1940' s of methods of producing 
vaccines by growing the microorganisms in embryonated hens eggs 
marked the beginning of rapid advances in the area of infectious 
disease therapy. The first of these vaccines were typhus vaccine 
and yellow fever vaccine. In 1955, a most significant change was 
initiated with the production of poliomyelitis vaccine by tissue 
culture techniques. These scientific advances have resulted in a 
vast increase in the volume and types of such products with an 
attendant major change of approach in industry to place greater 
emphasis on research. 

This makes it imperative for the Division to keep abreast of 
the constantly developing advances by augmenting its research facili- 



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- 3 - 
ties and by the development of new lines of research within its 
programs. 
Control Activities 

A system of licensing is the basis for the control of biological 
products. This system involves the issuance of both establishment 
licenses and product licenses, following the determination by the 
Division that prescribed standards for safety, purity, and potency 
have been met. These standards are set forth in regulations which 
are continually reviewed for adequacy in the light of new advances. 
Additional standards are formulated as new products are developed. 

A total of 275 biological products are now licensed. These 
are manufactured in 176 licensed establishments for which over 1,200 
product licenses are in effect. A major activity of the control 
program is the review of manufacturers' records of production and 
testing and the testing in the Division's laboratories of representative 
samples of these products. Tests, ranging from relatively simple 
sterility tests to complex, time consuming, costly potency deter- 
minations are carried out each year on over 3,000 individual lots of 
a wide variety of biological products. 

In addition to the inspection of manufacturing facilities and 
procedures prior to licensing, each licensed establishment is inspected 
annually to assure continuing compliance with prescribed standards. 
Close liaison is maintained with representatives of professional and 



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- 4 - 

technical staffs regarding proposed plans for new facilities and for 
modification of existing structures and equipment insofar as they 
affect the safety, purity, and potency of biological products. 

To assure that each licensed product is consistently acceptable 
and of uniform potency, standard physical reference preparations are 
developed and distributed to manufacturers and laboratories engaged 
in the standardization of biological products. Approximately 4,000 
vials are distributed annually by the Division. 

The control of biological products has been characterized from 
its beginning by the close cooperation between the Division and the 
manufacturers. Frequent meetings are held between members of the 
Division's professional and administrative staffs and groups of 
manufacturers who have common problems. In addition, from 150 to 
200 conferences are held each year with technical representatives 
of manufacturers to discuss production and testing problems peculiar 
to their own organization. Through such cooperation with the technical 
representatives of industry, as well as with independent investigators 
throughout the Nation, the Division frequently identifies potential 
problem areas in biologies production and control before serious 
difficulties arise. Division scientists, serving as members of 
international study groups, continue to take an active part in the 
World Health Organization's program for the development of international 
uniformity of biological products. Coordinated with the proposed 



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World Health Organization's cooperative effort to establish an inter- 
national laboratory standard of potency for cholera vaccine, DBS 
scientists are investigating improved methods for evaluation of the 
potency of cholera vaccine. It is only when such comparative data 
are available both in field and in laboratory studies that a standard 
of potency reflecting protective activity in human beings can be 
established. Major emphasis in this study is placed on standardization 
of technical details related to the performance of quantitative potency 
tests. 
Research Activities 

The control program of DBS is necessarily supported by an 
active research program, enabling the Division to keep abreast of the 
development of new and improved immunizing agents, and to prepare 
physical references as well as testing procedures for these products 
once they are ready for commercial production. 

This year considerable effort has been devoted to problems 
related to live poliovirus vaccine. While continuing a control and 
research program on killed poliomyelitis vaccine, extensive laboratory 
investigations have been carried out by the Division in an attempt to 
characterize, on a quantitative laboratory basis, the live poliovirus 
strains being used in field trials in this country and abroad. The 
fact that three separate sets of strains have been prepared multiplies 
the complexity of the problem. A continuing review of progress in 



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this area is made by the PHS Committee on Live Poliovirus Vaccine. 
Data, as they become available from these field trials, are subjected 
to evaluation with reference to the safety and effectiveness of the 
vaccine. Development of recommendations relating to the production 
and testing of live poliovirus vaccines has also continued. 

Changes designed to improve the killed poliomyelitis vaccine 
continued to be introduced. The Division utilizes the assistance of 
the Technical Committee on Poliomyelitis Vaccine to maintain close 
cooperation with the technical representatives of industry, giving 
attention to problem areas, both actual and potential. 

The desire of the medical profession for products which will 
immunize against several diseases simultaneously has been partially 
fulfilled during the year by the introduction of two multiple antigen 
products: 1) Poliomyelitis vaccine has been combined with diphtheria 
tetanus, and pertussis immunizing agents for use in pediatrics, thus 
providing a convenient means of broad immunization against four major 
diseases, 2) The combination of influenza viruses and the adenoviruses 
offers the advantage of protection against members of two classes of 
respiratory agents with a single course of inoculation. The anticipated 
field of usefullness for this combined antigen as demonstrated in field 
trials, is the reduction of acute upper respiratory infections in 
susceptible age groups such as military recruit populations. 

The preparation of multiple antigens is a complex process. The 
compatibility of the components and their stability in combination can 



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be determined only after searching study, followed by thorough clinical 
trials to determine their effectiveness. The Division has worked 
closely with industry and other research groups on these problems as 
well as the development of testing procedures and the modification 
of required standards essential for control of such products. 

Although progress in the development of a commercial measles 
vaccine has been slow, studies relating to the eventual preparation 
of a standard reference reagent, as well as standardization tech- 
niques appropriate for effective evaluation of such an immunizing 
agent, continue. Collaborative work is also being carried out with 
other research laboratories in the development and testing of experi- 
mental measles vaccines. Work on the standardization of gamma globulin 
for measles antibody content is also being pursued so that it can be 
used more effectively in the control of measles epidemics. 

The long-term study on the effects of storage conditions on 
albumin are being continued in order to determine the nature of the 
changes observed in liquid albumin stored at room temperature. Data 
observed during these studies reveal the need for refrigerated storage 
of such products. Technical data which has also been provided permit 
an extension of the dating period for one such product. 

As a result of studies on long-term preservation of red blood 
cells by freezing which demonstrated the possibility of using such 
cells successfully even after storage for a number of years, it has 



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- 8 - 
been possible to establish a special repository of extremely rare 
bloods for emergency use. The Division has recently stored 20 rare 
bloods by this method and the project is being expanded as additional 
rare donors become available. 

It is anticipated that the Division's program for 1961 will 
follow the same lines as it has taken during the past two years. A 
flexibility will be maintained which will permit direction of emphasis 
according to the needs arising from the development of new and improved 
biological products. An additional coordinating influence will be the 
occupancy of the new building which will occur during 1961. 



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SUMMARY OF OPENING STATEMENT 
by 
Assistant to the Director for International Affairs, 
National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
Scientific Activities Overseas (Special Foreign Currency Program)' 



Mr, Chairman and Members of the Committee: 

The objective of this program is the support of medical 
research in other countries through use of foreign currencies 
available under the terms of Section 104(k) of Public Law 430. A 
total appropriation authorization of $3,707,000 is being requested 
for this purpose. The research efforts to be supported with these 
funds will be directed toward the solution of disease and health 
problems which are of particular importance in the respective countries, 
but which also hold promise of contributing knowledge of value and 
significance to the advancement of medical research in the United 
States and the world generally. These research activities also will 
make possible the training of many younger scientists whose 
professional growth will add to the medical research resources of the 
world and the potential for greater progress in the future as well as 
provide additional areas of training for the scientists of the United 
States. 

The activities proposed for support through use of P.L. 400 funds 
have been developed from suggestions and proposals made by scientists 
and research investigators in the various categorical programs of the 



- 2 - 
National Institutes of Health. They represent an appraisal of 
research problems of major importance in those countries where 
significant balances of P.L. 430 funds exist. The final determination 
of the specific research activity that will be carried out will be 
dependent upon such factors as the number of qualified investigators, 
the character of existing facilities, and the development of 
appropriate collaborating arrangements with research institutions 
and authorities in the respective countries. When these factors have 
been fully ascertained, it may be necessary to shift the character, 
emphasis or type of these research activities from those upon which 
this summary estimate has been based. 

Specifically, the funds requested would support such coordinated 
activities as: (1) cholera research in India and Pakistan; (2) schisto- 
somiasis research in Brazil and Egypt; (3) studies of tropical 
diseases such as filariasis, toxoplasmosis, amebiasis in countries 
as India, Pakistan, Indonesia, Israel, and Brazil; (4) regional 
laboratories for virus research in Asia (India), the Middle East 
(Israel), Southern Europe (Yugoslavia), and Northern Europe (Poland); 
(5) comparative cardiovascular diseases research in India and 
Yugoslavia; (6) nutrition studies such as kwashiorkor in India and 
pellagra in Yugoslavia; and (7) cancer epidemiology studies. 

It is anticipated that projects to be developed with these 
funds would be handled either as grants or contracts, following 



- 3 

procedures normally applied in the National Institutes of Health's 
program. Other appropriate means of securing technical advice will 
be used, particularly the opinions of competent scientists and 
scientific bodies within the countries concerned. However, no 
project will be supported contrary to the wishes of the official or 
semi-official governmental body which is responsible for the over-all 
planning and coordination of research efforts in each country. The 
funds will be used only to support additive research and will not be 
used to substitute for the support which each country would normally 
put into such research efforts, or which would normally be eligible 
for support from dollar appropriations. Since the funds will be 
available until expended, each project, when approved, will have 
:unds allocated for the necessacy duration of the project, up to five 
years, as a means of insuring stable support. 



OPENING STATEMENT 
by 
Assistant L o the Director, National Institutes of Health, 
for International Affairs 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATES 
for 
'•Scientific Activities Overseas (Special Foreign Currency Program) 



Mr. Chairman and Members of the Committee: 

It is a pleasure to appear before you today on the behalf of 
this program, which has as its objective the support of medical 
research in several countries through use of foreign currencies 
available under the terms of Section 104(k) of Public Lav; 400. A total 
appropriation authorization of $3,707,000 is being requested for this 
purpose. The research efforts to be supported with these cunds will 
be directed toward the solution of disease and health problems which 
are of particular importance in the respective countries; in some 
instances this provides conditions and situations that are not 
available in the United States, but are important to study for their 
relevance to our problems. Thus, the program holds promise of. 
contributing knowledge of value and significance to the advancement of 
medical research in the United States and the world generally. The 
expanded research activities which will be made possible through the 
use of these funds will enable progress in the control and eradication 
Ol major disease and health problems and in the basic understanding of 
disease and disease processes. It will also make possible the training 
of many younger scientists in these countries whose professional 



- 2 - 
growth will add to the medical resources of the world and the potential 
for greater progress in the future, as well as provide additional areas 
of training for the scientists of the United States. 

I think it important, at the outset, to point out that the 
activities posed in this request represent the first venture of the 
National Institutes of Health in the support of research in foreign 
countries through the use of P.L. 480 funds. In 1950 the National 
Institutes of Health, in conjunction with other Federal agencies, 
requested the appropriation of $175,000 for the purchase of P.L. 430 
currencies to support four projects involving the translation of 
Russian and other literature and periodicals in the medical sciences. 
These funds were appropriated in the First Supplemental Appropriation 
Act of 1959, and in accordance with the direction of the President are 
being administered through the Science Information Service of the 
National Science Foundation (NSF). This program is now well under way. 

The authorization which is being requested this year, however, 
will be utilized for the conduct of medical research activities, The 
National Institutes of Health, under its regular operating 
appropriations, supports research in foreign countries through research 
grants, resulting from applications submitted by foreign scientists 
and investigators interested in securing U. S. support for their 
ideas. The approval of these grants, however, is made under a policy 
which limits support to those research projects which involve 



- 3 - 

activities of a character or quality which is not available to the 
U. S. The amount of National Institutes of Health support for research 
in foreign countries is therefore quite small at the present time, 
amounting to about $2,9 million in 1960. 

The activities proposed for support through use of P.L. 480 
funds have been developed from suggestions and proposals made by 
scientists and research investigators in the various categorical 
programs of the National Institutes of Health. They represent an 
appraisal of research problems of major importance in those countries 
where significant balances of P.L. 480 funds exist. We believe the 
investigation of these problems will contribute valuable knowledge 
to medical research in the U. S. and the world in genesal as well as 
be of benefit to the countries involved. We are also confident that 
the research personnel and facilities necessary for this work are 
available in the respective countries. We have not had the opportunity 
to make a final on- the-ground assessment of either problems or 
resources, nor the opportunity to discuss in detail with our scientific 
colleagues in these countries the details of many of the specific 
projects. The estimate submitted here, therefore represents our best 
judgement concerning the nature of the research which might be 
undertaken and the funds which will be required for its support. 

The final determination of the specific research activity that 
will be carried out in the several countries involved will be dependent 



- 4 - 
upcn such factors as the number of qualified investigators, the 
character of existing facilities, and the development of appropriate 
collaborating arrangements with research institutions and authorities 
in the respective countries. When these factors have been fully 
ascertained, it may be necessary to shift the character, emphasis or 
type of these research activities from those upon which this summary 
estimate has been based. This will be necessary in order to take 
maximum advantage of the research opportunities and resources 
available in the several countries. In selecting specific research 
projects to be carried out, effort will be made to choose those 
activities which may yield information of value to both the problems 
of local concern and to questions of interest to the United States. 
Many research projects will be linked with others in similar 
or dissimilar geographical regions against targets of common concern, 
e.g. virus diseases and atherosclerosis. Comparative investigations 
using epidemiological techniques will study areas where the incidences 
of diseases such as cancer, heart diseases, dental caries, and mental 
ailments ace either abnormally high or low. 

MECHANISMS FOR THE DEVELOPMENT OF RESEARCH PROJECTS 
It is anticipated that projects to be developed with these funds 
would be handled either as grants or contracts, following procedures 
normally applied in the National Institutes of Health's program. This 
means that all projects would be subjected to technical scrutiny and 



- 5 - 
evaluation by a "jury of peers 1 '' such as is available through the 
National Institutes of Health Study Sections. Other appropriate 
means of securing technical advice will also be utilized, particularly 
the opinions of competent scientists and scientific bodies within the 
countries concerned. No project will be supported contrary to the 
wishes of the official or semi-official governmental body which is 
responsible for the over-all planning and coordination of research 
efforts in each country. Cn the contrary, such groups will be used 
to the maximum possible extent in assisting in the design and 
organization of projects within their country. 

The funds will be used only to support additive research and 
will not be used to substitute for the support x^hich each country 
would normally put into such research efforts. Likewise these funds 
will not be used to support projects which would normally be eligible 
for support from dollar appropriations. Since the funds will be 
available until expended, each project, when approved, will have funds 
allocated for the necessary duration of the project, up to five years, 
as a means of insuring stable support. 

TYPES OF PROJECTS 

The following are examples to illustrate the disease problems 
and the research opportunities which may be realized through this 
program. 






- 6 - 

1. Choi era - -Choi era represents one of the few major bacterial 
epidemic diseases whose control has not yet yielded to modern scientific 
approaches. Experts in the field believe that a properly designed and 
supported research effort would produce the knowledge necessary to 
bring the disease under control. The funds requested herewith would 
support coordinated research activities in India and Pakistan. The 
projects would be a part of a total attack on cholera which would also 
include research activities in other countries, 

2. Schistosomiasis - -There is substantial evidence that this 
disease is of growing importance since the rapid development of 
irrigation schemes is providing new sources for the spread of the 
infectious agent and for the propagation of the snails which act as 
the intermediate host. 

The funds requested would be used to organize coordinated 
projects in Brazil (field trials of therapeutic and prophylactic agents), 
and in Egypt (systematic study of the epidemiology of the disease and 
of che intermediate hosts). These projects would also be organized to 
permit the study of cases particularly from the viewpoint of inter- 
relations between diet and the disease as well as certain clinical 
features of the disease, now imperfectly understood, such as liver 
cirrhosis and portal hypertension. 

3. Other Tropical Diseases —Studies of certain aspects of other 
important tropical diseases such as filariasis, toxoplasmosis, amebiasis, 



- 7 - 
kala-azar, Chagas ' disease, and malaria are planned. The studies to be 
undertaken would vary with the disease but would include testing of 
therapeutic agents, better diagnostic methods and evaluation and study 
of certain poorly understood features of the clinical disease. These 
studies would be possible in India, Pakistan, Indonesia, Israel, Poland, 
Yugoslavia, and Brazil. 

4. Virus Diseases --The influenza pandemic of 1950 demonstrated 
once again the global spread of a viral agent, and the benefits that 
are derived from adequate arrangements to observe its occurrence and 
distribution, its means and routes of spread. The World Health 
Organization and many national organizations and experts are unanimous 
in their conclusion that a world-wide network of regional laboratories 
is needed to acquire knowledge for the great variety of viral agents. 
The funds requested herewith would be used to provide basic support 
for such regional research laboratories in Asia (India), the Middle 
East (Israel), Southern Europe (Yugoslavia), and Northern Europe 
(Poland) . 

5. Cardiovascular Pis eases --Increasing evidence is accumulating 
that suggests that the type and amount of dietary fat is a major 
factor contributing to the incidence and severity of atherosclerosis 
and the diseases associated with it, such as coronary artery disease 
and cerebrovascular accidents. Two countries, India and Yugoslavia, 
contain population groups who use dietary fats almost exclusively of 






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- 8 - 
one type. Closely adjacent populations are available which use 
completely different types and amounts of fat. Yet these populations 
are otherwise similar as to genetics, physical environment, and 
socio-economic factors. This would be an excellent opportunity to 
gain further knowledge of widespread significance through properly 
designed epidemiological and ecological studies. 

6. Nutrition --To understand further the nature of nutritional 
deficiencies, and to understand better the function of the essential 
nutrients in basic life processes it is essential to study individuals 
suffering with nutritional diseases. Numerous specific examples of 
unusual research interest and opportunity can be cited, such as 
blindness from Vitamin A deficiency in Indonesia and India, kwashiorkor 
in India and many other countries, the unique naturally occuring 
deficiency of the B vitamin pantothenic acid in India, and pellagra in 
Yugoslavia. 

7. Cancer - -The opportunities to acquire further knowledge 
concerning environmental factors which may be related to the incidence 
of various forms of cancer exist in countries where P.L. 430 funds are 
available. Of particular interest are studies on the relationship of 
schistosomiasis and bladder cancer in Egypt, of protein deficiency 

and liver cancer in Indonesia, and of nutritional deficiencies and 
intraoral cancer in India. 



SUMMARY OF OPENING STATEMENT 
by 
Chief, Division of General Medical Sciences, 
National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"General Research and Services, Public Health Service" 



Mr. Chairman and Members of the Committee: 

This statement is on behalf of the Division of General Medical 
Sciences which receives its funds from the research and training 
grants portion of the General Research and Services Appropriation. 

This Division administers the grant programs of the National 
Institutes of Health for research in the sciences basic to medicine 
and biology, in environmental and public health, and in certain clin- 
ical sciences not covered by the programs of the Institutes. In 
addition, the Division administers the grant programs for training 
investigators in the basic biomedical sciences, provides fellowships 
for general research training and directs the NIH Center for Aging 
Research. 

The research responsibilities of the Division fall into six 
principal areas. The first two, Chem istry of Life Processes and 
Human Development , cover fundamental research in a number of areas 
crucial to medical progress. In recognition of the growing emphasis 
on, and need for, basic research, about half of the Division's total 
research funds go Into these categories. The other four categories 



- 2 - 
are Environmental Health , Public Health , the Clinical and Preclinical 
Sciences , and Methods and Tools of Science . In all six areas I am 
happy to report that during the past year the Division has taken 
major strides forward in promoting significant scientific achieve- 
ment. 

As greater emphasis has been placed on the national medical 
research effort, needs have continued to increase for the trained 
manpower to conduct this research, and to teach, in the basic sciences. 
In the Division's research training program, grants are made to re- 
search institutions to help increase the number of highly trained 
scientists undertaking investigative careers in ten major areas of 
academic medicine and public health: Anatomical Sciences, Bio- 
chemistry, Biometry, Embryology and Development, Epidemiology, 
Genetics, Pathology, Pharmacology, Physiology and Microbiology, In 
a related activity, the Experimental Training Grants program helps 
the medical schools develop new approaches to the training of medical 
students for research careers. To provide additional flexibility in 
the training program of the Division, research fellowship awards are 
made to individual scientists at various stages of their training in 
research. 

In the field of aging, the NIH Center for Aging Research has 
actively continued its assignment of stimulating and coordinating 
research and training in gerontology, both through grants to non- 
Federal institutions and through direct research by all of the 



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- 3 - 
Institutes of NIH. The total NIH support of extramural projects re- 
lated primarily to aging was over $2 2 000,000 in 1958; $4,133,980 
in 1959; and approximately $8,600,000 at present. The number of 
individual extramural projects has increased from 131 to approxi- 
mately 273. Projects secondarily related to aging today total 374 
and amount to approximately $5,800,000 a year. These figures indi- 
cate substantive progress in answering many questions about aging, 
but much more work needs to be done, and we are continuing our ef- 
forts to stimulate research in this field. 

In conclusion, Mr„ Chairman, the appropriation request for the 
Division of General Medical Sciences for 1961 is a total of 
$44,638,000 as compared with the appropriation of $43,189,000 for 
I960. This allowance for 1961 will provide for the continuation 
of 1960 program levels in all activities and will permit some increase 
in grants for research projects. This request for 1961 is distrib- 
uted among program activities as follows: 

Research projects........ $26,446,000 

Research fellowships 5,310,000 

Training . . . c 11 ,540,000 

Review and approval of grants ...... 1, 34?. ,000 



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OPENING STATEMENT 
by 
Chief, Division of General Medical Sciences, 
National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"General Research and Services, Public Health Service" 



Mr. Chairman and Members of the Cotrmittee: 

My statement is on behalf of the Division of General Medical 
Sciences, which receives its funds under the research and training 
grants portion of the General Research and Services Appropriation. 
The other division supported by this appropriation, the Division of 
Biologies Standards, has been discussed by the Director of the National 
Institutes of Health in his opening statement. 

The Division of General Medical Sciences administers the grant 
programs of the National Institutes of Health for research in the 
sciences basic to medicine and biology, in environmental and public 
health, and in certain clinical sciences not covered by the programs 
of the Institutes. In addition, the Division administers the grant 
programs for training investigators in the basic biomedical sciences, 
provides fellowships for general research training and directs the NIH 
Center for Aging Research. 

The research and training programs were established, and have 
grown at an appreciable rate, as the result of needs, particularly in 
certain basic science areas, which could not be adequately met by the 
disease-oriented, categorical programs of the Institutes. 



- 2 - 

In recent years there have been remarkable achievements in 
learning more about the fundamental physiological and biochemical 
processes of man and more about the nature of life itself. New dis- 
ease conditions have been defined and new drugs and other new forms 
of therapy have been developed -- fundamental steps which are crucial 
to the advancement of medicine. These new biological and medical 
accomplishments have served at the same time to reveal previously un- 
explored areas which the scientists now must study. 

Concurrently, there has been a commensurate growth in the need 
for training more researchers in the basic biomedical sciences. It 
is quite plain that we should seek to improve both the quantity and 
quality of research manpower if the level of research itself is to be 
adequate. 

These needs for increases in both basic biomedical research 
and basic research training were recognized by the National Institutes 
of Health in the establishment of programs in the Division of Research 
Grants. From fiscal years 1956 to 1959 these programs grew from a 
level of $5,000,000 to $26,721,659. They were transferred to the 
Division of General Medical Sciences when it was established in July 
1958. For fiscal year 1960 a budget of $43,189,000 was provided to 
cover our responsibilities for basic research and for research in en- 
vironmental and public health and in certain applied medical sciences. 

Along with these other organizational moves, the Center for 
Aging Research, which serves as a focal point for all NIH grant 



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activities in aging, was transferred from the National Heart 
Institute to become a component of the Division of General Medical 
Sciences. 

My remarks today, therefore, will be concerned with these three 
areas of the Division's program: research, research training and aging, 

RESEARCH 

In the 18 months since the Division was formed, and particu- 
larly in the past year, our research responsibilities have been 
organized into six principal areas. I am happy to report that the 
Division has taken major strides forward in promoting scientific 
achievement in each of these six areas. 

First are the two important basic research fields which consti- 
tute the foundation of most other biological and medical areas: 

(1) THE CHEMISTRY OF LIFE PROCESSES. There are few problems 
in all of science more exciting than the study of the nature of life 
itself: how non-living chemical substances such as amino acids are 
joined together to form the protein of all living matter; under- 
standing how enzymes act to facilitate chemical reactions in the 
body; how pharmacologic drugs act on man; and how genes -- the all- 
important carriers of heredity — are formed. These are all questions 
to which the Division grantees are addressing themselves. About 
one-fourth of our research grant funds are devoted to this area. 

(2) HUMAN DEVELOPMENT. The biology of human development is 
the second major concern of DGMS. Here our attention is devoted to 



- 4 - 
the development of the organism from conception through embryological 
stages to birth and on through childhood and adulthood to old age. 
The sciences of genetics, embryology, cell biology and physiology are 
paramount here. This area comprises about one-fourth of our grant 
program. About half of our funds, therefore, are going into basic re- 
search areas. 

Next, let me mention two broad fields of study relating the 
individual to his environment: 

(3) ENVIRONMENTAL HEALTH is currently receiving well-deserved 
attention from scientists and from the public. The dangers to health 
stemming from our environment are frequently not so dramatic or dis- 
cernable as the effects of cancer or heart disease, but they possess 
the insidious characteristic of being always with each and every one 
of us, in the water we drink, in the air we breathe, in the food we 
eat, and in the lurking hazards to which man exposes himself in his 
work, travel and play. Research on these topics comprises one- fifth 
of the DGMS program. 

(4) PUBLIC HEALTH. The health resources to which a doctor or 
patient can turn when illness occurs are a major focus of public 
health today. Research is needed on the prevalence and epidemiolog- 
ical characteristics of disease; what kind of medical services are 
most effective, most needed, or most economical; and what forms of 
rehabilitation and nursing are most satisfactory in returning a pa- 
tient to productive life. 



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In addition, the Division provides grant support for two areas 
of medical science; the substance of which crosses categorical dis- 
ease lines: 

(5) THE CLINICAL AND PRE-CLINICAL SCIENCES supported by EGMS 
include anatomy, endocrinology, general surgery, anaesthesiology, 
orthopedics, pediatrics, and others. 

(6) METHODS AND TOOLS OF SCIENCE, Through this program NIH 
promotes research on improving the techniques and tools of scientific 
achievement: the development of new methods for biological measure- 
ment and of new instrumentation, studies of how to make the medical 
literature more readily available and useful to scientists, support 
of certain specialized meetings of scientists to speed up the ex- 
change of research findings and problems, and the preparation of 
specialized biological handbook materials. 

Slightly less than a third of our funds go into these latter 
three areas. 

During the past three years, the Congress has recognized the 
importance of these six areas by making progressively larger appro- 
priations for research grants. The appropriation for fiscal year 
1958 was $9,468,000; for 1959, $16,621,000; and for 1960, $23,559,000, 
These funds have permitted the support of 645 research projects in 
1958, 1,065 in 1959, and an estimated 1,470 in 1960. The distrib- 
ution of these grants by area of interest during the present fiscal 
year is shown in the following table: 



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Estimated Number Estimated 
Field of Research of Research Projects Cost 

FY 1960 FY 196 

Chemistry of Life Processes 415 $5,561,000 

Human Development 534 6,110,000 

Environmental Health 255 4,704,000 

Public Health 92 3,728,000 

Clinical & Pre-Clinical Sciences 97 1,682,000 

Methods and Tools of Science 77 1.774,000 

1,470 23,559,000 

The increase in research grant funds available to us during 

fiscal year 1960 has permitted orderly expansion of the support of 

high quality research. The review of applications by Study Sections 

and by the National Advisory Health Council has remained as rigorous 

as in the past, and with the application of the President's Criteria 

has possibly been even more rigorous in borderline cases. The large 

increase in expenditures, therefore, is simply a reflection of the 

fact that many more applications of high quality were received than 

in preceding years. 

Of our total expenditures for research grants this year, 

$647,611, or three percent of our funds, is going to support research 

projects outside the United States. This involves 37 grants. 

During the coming year the Division plans to devote special 

attention to the support of grants in certain areas of particular 

scientific or public concern. These include: 



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- 7 - 

1) studies of the effectiveness and availability of medical 
care and services, especially for the aged, 

2) biomedical engineering, the adaptation of tools and concepts 
from the engineering sciences for use in medicine and biology, 

3) the stimulation of much needed studies of comparative anat- 
omy, in order that we may more effectively and speedily utilize the 
findings of animal research in the control and prevention of human 
disease, 

4) the effects of toxic agents on man, whether these originate 
as air pollutants, water pollutants, food contaminants, or industrial 
materials. 

Beyond these, special note should be made of the increasing 
frequency with which NIH staff are consulted with respect to the 
establishment of major research centers in which a variety of scien- 
tists may bring their various skills and knowledge to bear on a 
single topic or problem. The Division of General Medical Sciences 
has been charged with the responsibility of administering grants to 
establish a limited number of clinical research centers. It also 
currently provides support, or has proposals under review for support, 
of research centers of regional or national importance in the field 
of aging, genetics, cell biology, and biomedical engineering. It is 
hoped that these new activities will provide a sound pattern for the 
development of regional research resources of many kinds. 

With regard to accomplishments in specific areas of research 



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in the past year, I understand that the document "Highlights of Prog- 
gress of Research in General Medical and Biological Sciences" will be 
presented as in past years, but I think that at this point the Com- 
mittee might be interested in a' very few selected examples of the 
type of work the Division is supporting. 

In the basic research areas, one scientist has produced some 
remarkable results in his experiments with proteins, a fundamental 
component of living matter. In earlier work this scientist reported 
making a primitive protein from combinations of 18 amino acids. 
More recently he has reported a successful effort to convert the 
proteinoids into spherules which closely resemble cells. The work 
may be of tremendous significance in understanding how life was 
first formed on the earth and how primitive proteins became living 
cells. 

A work significant in diagnosing kidney disorders has been re- 
ported by a scientist studying renal aminoaciduria. He has found a 
practical method, using paper chromatography, for analyzing amino 
acid concentrations in a urine sample, and has reported that patterns 
of the different concentrations help to indicate the presence and 
nature of certain diseases. 

Another scientist has made some noteworthy advancements in 
studies of the effects of extreme cold on animals and human beings. 
He reported the successful reanimation of mice cooled to less than 
32 degrees (Fahrenheit) and progress in determining the most effective 
techniques for resuscitation by using heat and combinations of air, 



- 9 - 
oxygen or mixtures of oxygen and carbon dioxide. The work has im- 
portance in aiding the revival of persons suffering from extreme 
cold. It also has considerable significance with respect to the in- 
duction of low body temperatures as a therapeutic measure. 

In the field of food technology, one scientist has been study- 
ing the results of combinations of certain insecticides on foods. He 
has used approved insecticides, experimenting with what could happen 
if, for example, a person ate one insecticide from an apple and an- 
other insecticide from some grapes. In three out of 15 combinations 
he found that the toxicity was potentiated greatly, enough in fact 
to kill the test animals. The work obviously points to the need for 
much more research in this area. 

Other work includes the finding that wounds, closed immedi- 
ately after exposure to certain low levels of irradiation, will heal 
normally; that axillary granuloma can be caused by the metal zirco- 
nium as a constituent of anti-perspirant preparations; that the 
fetal electrocardiogram is quite effective in diagnosing multiple 
pregnancies. We also have contributed to medical technology in the 
development of methods for measuring the motility of the esophagus; 
a new method of bronchography; two instruments for measuring and 
analyzing acids and aerosols in the air; and a new, small instrument 
which can be attached to a patient's chest to measure his heart 
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Funds totaling $26,446,000 are being requested for research 
grants during 1961, an increase of $2,887,000 or about 12 percent 
over last year. 

TRAINING 

As greater emphasis has been placed behind the research effort, 
shortages have continued to mount in trained manpower to conduct this 
research, and to teach, in the basic health-related sciences. 

There are several aspects to the overall problem: 

(1) The general need for investigators and teachers in the 
basic sciences exceeds the supply. 

(2) Investigations in the clinical fields not only are depend- 
ing more heavily than ever on advances in the basic sciences, but are 
continuing to draw personnel from the basic areas, commonly because 
of the attraction of higher salaries, 

(3) Young physician- investigators, recognizing needs for basic 
science training, have put greater demand on university and pre- 
clinical science departments for appropriate opportunities. 

(4) Medical educators are calling for an expanded medical 
teaching program if the nation's supply of physicians is to remain 
adequate for the health needs of the nation's expanding population. 

The evolving nature of modern medical and biological research 
and teaching, therefore, has added significantly to the already grave 
obligations of the teachers and scientists in the basic fields, which 
themselves have suffered a lack of adequate attention and support in 
the past. 



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The importance of meeting these needs is emphasized by the fact 
that it takes between five and ten years to prepare a scientist for a 
productive career; so that training programs undertaken now are 
planned to try to meet conditions in 1965 or 1970 when the require- 
ments will be even more critical than at present. 

The needs to support the training of research scientists have 
long been recognized by the National Institutes of Health with train- 
ing programs in specific fields, such as psychiatry, neurology, 
rheumatology and cardiovascular diseases. Several years ago, as we 
mentioned earlier, NIH launched its programs to help support the 
training of investigators in the fundamental sciences. The Division 
of General Medical Sciences became the principal NIH unit for these 
research training and fellowship programs when it was established in 
July 1958. 

The programs have the following goals: (1) To strengthen the 
research training institutions and increase their potential for devel- 
oping teachers and scientists; (2) To aid the flow of competent, 
highly-motivated students through the graduate schools of the univer- 
sities; (3) To expand the opportunities for intensive training of 
predoctoral and postdoctoral candidates in additional research insti- 
tutions wherever appropriate; and (4) To encourage and support the 
greater utilization of trained manpower to improve the teaching and 
training functions of the universities and research institutions. 

I will discuss first the training grant program including the 



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- 12 - 
Experimental Training Grants Program, and then fellowships, with 
special emphasis on the Senior Research Fellowship program. 

Research Training -- This program provides grant funds to 
public and private nonprofit institutions, such as the medical schools, 
for the establishment, or improvement of graduate research training. 
The purpose is to increase the number of highly- trained scientists to 
undertake investigative careers in academic medicine and public health. 

Although projects may be supported in any basic biomedical or 
health-related science where scientific manpower shortages exist, 
regular programs in ten areas are being operated by Division of Gen- 
eral Medical Sciences at present. Two of these of long-standing 
importance, Epidemiology and Biometry, were in existence at NIH for 
some years before being assigned to Division of General Medical 
Sciences. During 1959, we established seven more, in the Anatomical 
Sciences, Biochemistry, Embryology and Development, Genetics, Path- 
ology, Pharmacology, and Physiology, and we currently are establishing 
a program in Microbiology. Each program functions under the guidance 
of Training Committees composed of non-Federal scientists and other 
experts in those particular research and training fields. 

At present (February) these programs are supporting a total 
of more than 286 research training activities in universities and 
other institutions across the nation. 



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- 13 - 
The following figures will give an idea of the growth of the 
work in recent years: 
Year Appro p riation Nu mber of Training Projects Supported 

1958 $2,962,000 75 

1959 6,040,000 163 

1960 13,040,000 315 

By the end of fiscal year 1960 there will be an estimated total 
of more than 1,700 graduate and postdoctoral students in a research 
training status. Already these awards have had a marked effect in 
helping provide stability to the basic science departments of many 
schools, by allowing an increase of postdoctorate training opportun- 
ities, and by improving the quality of the end product -- the trainee. 

The very existence, of these training awards has led to other 
and somewhat unexpected dividends. There are indications that the 
availability of funds has stimulated additional numbers of students 
into serious consideration of research and academic careers. Also, 
the improvement of facilities and faculty interest for graduate train- 
ing indirectly has effected marked improvements in undergraduate 
teaching; and the prestige attached to the receipt of one of these 
highly competitive awards has stimulated departments to increase their 
efforts in obtaining and selecting high caliber trainees. 

The training program, then, has already met its initial aims; 

(1) There has been an increase in the total number of depart- 
ments, capable of turning out well-trained scientists; 

(2) The quality of all training programs has been markedly im- 
proved ; and 



- 14 - 

(3) There has been a significant increase in the number of com- 
petent trainees who have recently completed or are completing their 
postdoctoral research training and are thus available for academic 
careers at junior or intermediate staff levels. In particular, the 
appearance of well-trained basic scientists in certain shortage fields 
has increased the demand for such scientists through the demonstra- 
tion of their effectiveness in contributing to new areas of research. 

Research training in many of the basic and health-related 
sciences is in a continual state of transition, which flows from the 
recent and significant advances in related areas of research, in 
instrumental techniques and in experimental design. Our training 
grants have allowed the placing of special emphasis on certain of the 
key or critical areas, where timing is important, by providing the 
needed support and impetus for the growth of these fields as research 
sciences. 

For fiscal year 1961, funds in the amount of $11,040,000 are 
requested for the research training program. 

Experimental Training Grants Program -- This program, initiated 
in 1957, has enabled 13 medical schools to carry out experimental 
efforts aimed toward the improved development of medical scientists 
and teachers. More specifically, the funds enabled the schools to 
adapt in their curricula new features considered desirable in keeping 
pace with the rapid increases in medical knowledge and the rising 
standards of medical practice. Specially chosen students are given 



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- 15 - 
special research training to develop their abilities and to stimulate 
their interest in research and teaching careers. 

This year more than 1,200 well qualified and highly selected 
medical students have been attracted into research programs early in 
their careers. Some 600 of these students have chosen to study and 
work under the direction of pre-clinical science departments. The re- 
search fields of anatomy, biochemistry, pathology and physiology are 
particularly well represented. 

As an example of the stimulation to private funding given by 
Federal awards, one school reported that a private foundation has re- 
cently provided salaries for four full-time faculty members to expand 
its potential for research training. 

During the past year a critical evaluation of this program has 
been undertaken by an expert committee of non-Federal scientists. 
This study will provide the definitive information we shall need when 
we discuss with this committee the advisability of expanding or re- 
stricting this program. Early progress reports from the study suggest 
that the program is extremely valuable and that next year we shall 
probably recommend its expansion and establishment on a permanent 
basis. 

■ 

The budget proposes $500,000 for the program in 1961, the same 
as in 1960. 

The program is the subject of a Special Report which is being 
provided to the Committee. 



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Resear ch Fellowships -- In contrast to the research training 
grants, which are made to institutions, the research fellowship 
awards are made to individuals in order to maintain a measure of 
flexibility in national programming for the support of research 
training. The fellowships therefore are considered complementary to 
the training awards to institutions. Through five major categories 
of awards it is possible to provide spot support for newly developing 
areas and to provide special emphasis at a number of education levels 
and situations. 

The fellowships serve to give students in schools of medicine, 
dentistry, nursing, and public health, an orientation to, and an 
appreciation of, basic research; to allow foreign scientists to par- 
ticipate in the research opportunities in this country, and to 
provide firm, long range support for young academic staff members 
with a primary interest in research. 

For the five fellowship areas the budget provides funds total- 
ing $5,310,000 during 1961, the same as in 1960. 

I will discuss each of these five areas in more detail: 

Regular Research Fellowships -- This program is designed to 
help increase the pool of scientists in basic biomedical sciences 
and related areas. Research training on a full-time basis in fields 
such as experimental pathology, pharmacology, physiology, biochem- 
istry and genetics is provided for selected, promising fellows at 
predoctoral, postdoctoral and advanced or special levels. 



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The predoctoral fellowships emphasize the type of general re- 
search training represented by graduate curricula and thesis require- 
ments in the basic biological and health-related sciences. The 
postdoctoral fellowship makes provision for the increasingly special- 
ized research and teaching experience of promising graduates in the 
years immediately following the receipt of a doctoral degree. 

The development and emergence of new areas in research has kin- 
dled interest in many senior, established scientists who may lack 
certain basic information or techniques needed to switch attention to 
new research fields. Special fellowships are designed to help these 
scientists obtain training and experience in these new areas „ 

It is expected that approximately 216 new regular fellowships 
will be awarded during 1960, aside from continuations. The same 
level of activity is planned for 1961, with the budget remaining at 
$1,035,000, the same as in 1960. 

Postso phomore Research Fellowships — The changing character 
of the medical and dental schools is attested to today when the supe- 
rior student is encouraged to drop his regular work for as much as 
three years to carry out full-time research studies in a basic or 

pre-clinical science department before continuing his regular medical 
studies. The postsophomore fellowship program supports such training 
for a limited number of medical or dental students who are selected 
by their schools. These fellowships are awarded for a one, two or 
three-year period, usually immediately following the candidate's ■ 



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- 18 - 
completion of his pre-clinical studies. They are highly regarded by 
the training institution as an effective means for the early identi- 
fication of top flight research personnel and their recruitment into 
fundamental studies, or for the training of physicians with compe- 
tence in medicine and in medical-related investigation. 

The increase from $435,000 in 1959 to $575,000 in 1960 permit- 
ted 25 additional new postsophomore fellowships to be awarded and 
will bring the total for the year to more than 150. A program at 
the same level of $575,000 is projected for 1961. 

Part-time Student Fellowships — As a companion program to 
the postsophomore fellowship, these awards are limited to the sup- 
port of students undertaking part-time research training in schools 
of medicine, dentistry, nursing, and public health. It is a par- 
ticularly effective recruiting device for basic science research, 
since many capable students who desire such training may hesitate 
or be unable to drop their studies for the full year or more re- 
quired by other awards. The program has been well received by 
participating schools, since many students thus have been stimulated 
into additional research training and study, and have been able to 
compete successfully for further fellowship or training awards. A 
staff study is underway to identify further the effectiveness of this 
program by following the subsequent successes of part-time fellows in 
the fellowship and research project competition. 

The $300,000 appropriated in 1960 is permitting the support 



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and research training of more than 460 new part-time fellows and a 
program of the same size is planned in 1961. 

Fello wships jfor scientists Jrom other countries -- These 
fellowships are awarded to scientists from abroad who desire a year 
of advanced study and collaboration with outstanding scientists at 
the NIH and at other medical research centers in this country. Since 
progress in basic medical research is made on an international basis, 
this award promotes a direct and mutual exchange of ideas on technical 
accomplishments and scientific outlook. Frequently the international 
fellow is well-equipped to make fresh and valuable contributions to 
our programs as well as to receive the favorable benefits represented 
by experience with the modern technical and scientific activities of 
our research scientists. 

Candidates for these awards are proposed by a selection com- 
mittee within each country, with final selections being made by the 
NIH. In 1960 the $400,000 allocated to this program has permitted 
the appointment of nearly 60 carefully selected and screened post- 
doctoral fellows, and the same size program is planned for 
continuation in 1961. 

Senior Research Fellowships -- This keenly-competitive and 
highly-regarded award program was established to provide support for 
academic scientists in the pre-clinical departments of medical and 
dental schools and schools of public health. Candidates who show 
high promise or exceptional competence are selected on the basis of 



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their ability to establish and maintain a strong nucleus of research 
activity within these departments while developing themselves as well 
rounded academic leaders. 

These awards have the additional advantage of helping to re- 
lieve the critical shortage of basic investigators in the pre-clinical 
departments, as well as providing stability during a critical stage 
in the careers of these scientists — that is, the period between the 
completion of their postdoctoral training and their eligibility for 
permanent senior appointments. 

In addition the quality of teaching and investigative work 
conducted by personnel located in clinical departments has become an 
important feature in modern academic medicine and in the application 
of new knowledge gained through fundamental research. In 1961 we 
plan to accept applications from clinical departments. 

The 1960 appropriation of $3 million is providing support for 
95 new senior fellows, bringing the anticipated total to be supported 
to 240. The budget proposes continuation of the program at the same 
level in 1961. 









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- 21 - 

CENTER FOR AGING RESEARCH 

The Center for Aging Research, which became a component of 
the Division of General Medical Sciences a year and a half ago, 
has the purpose of stimulating and coordinating research and train- 
ing in gerontology both through grants and through direct research 
in this field by all the Institutes of NIH. 

National and international interest in the field of aging 
and in research in aging is, of course, continuing to mount 
rapidly. 

With regard to research in aging, the growing interest is 
reflected in the greater number of scientists who have applied for 
NIH grants to carry out work in research in aging in nearly every 
medical and biological discipline. Total NIH grant support of 
research projects classified as related primarily to gerontology 
was $464,000 in 1957; $1,779,000 in 1958; $3,221,546 in 1959 and 
a figure of $6,804,000 is estimated for 1960. 

If we include, for 1960, those projects classified as 
secondarily related to aging, the total will be over $11,000,000. 
The intramural work carried out directly by NIH personnel, princi- 
pally in the National Heart Institute and the National Institute of 
Mental Health, will amount to another $1,000,000 for an over-all 
total of approximately $12,000,000. 

The Center for Aging Research carries out its work in close 
coordination with all the Institutes and with other bureaus and 



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- 22 - 
divisions of the Department of Health, Education, and Welfare, 
including the Special Staff on Aging in the Office of the Secretary; 
the Health of the Aged Section in the Chronic Disease Program of 
the Bureau of State Services; the Public Health Service Committee 
on Aging. The Center is working with the Atomic Energy Commission 
in supporting studies of the similarities between radiation effects 
and physiologic aging. 

Full cooperation is being given to the Federal Council on 
Aging and to the White House Conference on Aging. In the latter 
instance, the Center for Aging Research staff is providing technical 
assistance in planning the agenda of the conference. 

Beyond this work with official agencies, we have continued 
to cooperate with the great number of private organizations in the 
field of aging. 

In addition to smaller grants, as you know, NIH has made 
grants for two large interdisciplinary research projects in aging, 
one to Duke University in 1957, and the other to the Albert Einstein 
College of Medicine in 1958. In November 1959 the Duke Center for 
the Study of Aging sponsored its First Annual Conference on geron- 
tology. Papers were read on subjects ranging from "General Aspects 
of Geriatric Surgery" to "Financial Aspects of Aging." 

This Conference is the most recent of a number of important 
contributions the Duke project already has made to research in 
aging. Several research papers on a wide range of aging problems 



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- 23 - 
have been contributed by the Duke scientists to the professional 
literature, and we are looking forward to greater progress in the 
forthcoming year. At this point, 20 separate projects have been 
initiated under the Duke program. It may be of interest to the 
Committee to know that after NIH made its grant to Duke, the Ford 
Foundation provided the University with an additional $200, 0C0 for 
studies on the socio-economic aspects of aging. 

The Albert Einstein project, a year younger than the Duke 
program, has completed its work in renovating research laboratory 
space for the aging work and has moved from the "tooling-up" phase 
into the "tuning-up" phase. Whereas the Duke project is university- 
wide in scope, the Albert Einstein program is concentrated in the 
Medical School where intense attention can be given to patients in 
the Nathan Van Etten Hospital. The City of New York has made a 
large ward there available to the program and is providing the basic 
medical care needed by the patients. The Albert Einstein project is 
seeking a high level of flexibility in its investigations, with 
great emphasis on the effort to cut across the dividing lines of 
disciplines and departments. 

The Duke and Albert Einstein projects have attracted national 
attention and we have received applications from a number of other 
groups interested in establishing similar multidisciplinary aging 
research projects in university settings. 



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- 24 - 

In addition, of course, the CAR staff is continuing to 
encourage more high-caliber individual investigators to work in the 
field of aging. I reported before this Committee last year that 
we were stimulating additional study into the three broad areas 
which are embraced by research in aging: the behavioral and social 
sciences , to bring more work to bear in the mental health problems 
of older people; the clinical sciences , to help overcome the diseases 
which so often characterize old age; and the biological sciences , 
to answer very basic questions related to the exact nature of the 
biological process of aging and its relationships with disease. 

We have made considerable progress in the past year in 
encouraging research along these three lines, but more needs to be 
done. Among other plans in the forthcoming year for stimulating 
additional research, the Center for Aging Research plans to assist 
and cooperate with the Fifth International Congress of Gerontology 
to be held in San Francisco in August 1960. 

Although aging will be the subject of a Special Report to be 
provided the Committee, I should like to cite two or three examples 
of the findings that have come out of our research in aging in the 
past year. 

One investigator has found that a factor closely resembling 
the "juvenile" hormone exists in human tissue. This hormone was 
discovered in insects, and serves to control the development of the 
insects by governing the proper timing of growth from the pupa, or 



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- 25 - 
cocoon, form, into maturity. It has been found that when this 
hormone is injected into certain insects it will allow some growth 
to continue, but generally it maintains the insects in a juvenile 
state -- having the effect of lengthening the life-span by slowing 
down maturity. More research is being carried out to determine 
whether, in humans, the hormone is simply a physiological curiosity 
of little significance, or whether it has a bearing on the manner 
in which man grows old and on the speed with which he ages. 

With respect to the common infirmities of older persons, 
there has been a clear demonstration in recent years that the 
application of intensive rehabilitation techniques will greatly 
reduce the disability resulting from these Infirmities. We do not 
have any good quantitative measures, however, of the percentage of 
older people who can be benefited by rehabilitation techniques, of 
the kind and amount of rehabilitation service that is needed, of 
the degree of improvement that can be achieved, or of the cost. 

In a New York project, investigators are carrying out 
intensive studies to answer these questions. Working with groups 
of patients in nursing homes, they are developing measures of 
disability which are particularly applicable to this group. They 
are using rehabilitation teams to treat some of the patients within 
the nursing homes, while other groups of patients are transferred 
to rehabilitation hospitals for more intensive therapy to see if 
the results of such therapy are significantly better. They plan 



- 26 - 
to follov; all of the patients for a reasonable period after 
termination of specific therapy to see how long the effects last. 
This study gives promise of producing information that will be of 
termendous value in guiding those who are charged with the responsi- 
bility of taking care of older people. 

The third study, of particular importance to the mental 
health of older people, has .shown interesting relationships between 
blood pressure and the electroencephalogram patterns. Among older 
persons generally the electroencephalogram pattern is more irregular 
than among younger people. This study has shown, however, that 
older persons with high blood pressure have a more regular pattern 
than people of the same age with normal blood pressure. This study 
is being continued and if the electroencephalogram patterns are 
found to be correlated with actual brain functioning, the investi- 
gators may come to the conclusion that a degree of high blood 
pressure is sometimes a protective mechanism, rather than being 
wholly bad. 

These three studies illustrate the scope of research activity 
in the field of aging: a study of the biochemistry of aging, a 
study of the medical- social treatment of older persons, and a study 
of clinical findings. 



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- 27 - 

CONCLUSION 
In conclusion, Mr, Chairman, the appropriation request for 
the Division of General Medical Sciences for 1961 is a total of 
$44,638,000 as compared with the appropriation of $43,189,000 for 
1960. This allowance for 1961 will provide for the continuation of 
1960 program levels in all activities and will permit some increase 
in grants for research projects. This request for 1961 is distri- 
buted among program activities as follows: 

Research Projects $26,446,000 

Research Fellowships - 5,310,000 

Research Training Grants 11,040,000 

Experimental Training Grants 500,000 

Review and approval 1,342,000 

Total $44,638,000 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Cancer Institute, 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
196l ESTIMATE 
for 
"National Cancer Institute" 

Mr. Chairman and Members of the Committee: 

The research and related programs of the National Cancer 
Institute achieved their highest level of operation within the 
past year. The budget request for 1961 of $88,869,000 will allow 
continuation of these activities at their present level and will 
permit some increases in grants for research projects and in dir- 
ect research operations. 

A brief look at progress in cancer research in the last 
decade shows not only a steady advance in fundamental knowledge 
of the nature of cancer but also several specific research paths 
that make us optimistic about the future. Evidence that cancer 
is a manifestation of a basic flaw in the chemistry of the cell 
points to the possibility that science will discover new and 
vastly effective ways to eliminate cancer by prevention, early 
diagnosis, and curative drug treatment. The increased knowledge 
of the role of viruses in the production of cancer in animals and 
demonstration that some animal tumors can be prevented by vaccina- 
tion strongly supnort the hope that at least some forms of human 
cancer may also be virus diseases against which vaccination will 



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-2- 

be effective. Development and application of the cytologic 
test for early detection of cancer of the uterine cervix can 
lead to the virtual elimination of mortality from this form 
of cancer. Cancer chemotherapy has assumed a place of major 
importance. Although curative drugs still are lacking , many 
cancer patients — especially those with acute leukemia- -have 
been afforded longer, more comfortable lives by the use of 
drugs . 

Numerous laboratory and clinical studies by scientists 
and grantees of the National Cancer Institute in the past year 
have focused attention on a number of promising anticancer drugs 
and on potentially better methods of administering drugs to 
patients. The program of the Cancer Chemotherapy National Ser- 
vice Center has continued to expand, and 109 drugs are now under 
clinical evaluation in studies involving some 7,700 patients. 
Approximately 50,000 materials per year are being tested in 
animals to identify new active drugs. Serious attention is being 
given to attempts to improve the correlation between the res 'Its 
of animal studies and clinical experience. 

The Institute's diagnostic research program which started 
with cervical cytology and which has been shifted to new approaches 
is proceeding satisfactorily. Now in its second year is the can- 
cer control program of the Bureau of State Services, which is in- 
tended to speed the application of proved cancer control measures 






-3- 

in the general population, and sound initial steps have been 

taken to now move ahead with the program. 

Interest in the study of viruses as cancer causing agents 
continues to be high. Emphasis has been placed on studies of 
the relationship of viruses to human cancer. Much additional 
information on viruses in animal tumors was accumulated, includ- 
ing discovery of a new viral mouse leukemia. The National Cancer 
Institute has been instrumental in stimulating research on the 
virus-cancer question and is now supporting 110 grants in this 
area at a cost of nearly $ h, 000, 000, 

The comprehensive program of research and related activities 
being conducted and supported by the National Cancer Institute is 
steadily increasing knowledge of the nature, cause and prevention, 
diagnosis, and treatment of malignant disease. As these endeavors 
continue to yield new knowledge, and as this is gradually brought 
to practical application, the control of human cancer will become 
increasingly complete. 



OPENING STATEMENT 

by 

Director, National Cancer Institute 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"National Cancer Institute" 



Mr. Chairman and Members of the Committee: 

It is a distinct pleasure to come again before this Committee 
to review the research and related programs of the National Cancer 
Institute. I am sure the Committee will share with me the belief 
that these activities have brought us substantially closer to the 
goal of full and effective control over this awesome threat to the 
health and welfare of people everywhere. 

Before proceeding with a report to you on the Institute's 
diverse activities, I should like to take note of the passing, 
within the past year, of three of this Nation's outstanding 
contributors to cancer research. Two of these men were struck 
down suddenly in the fullness of their careers. Dr. Jesse P. 
Greenstein, Chief of the Laboratory of Biochemistry of the 
National Cancer Institute, died of a stroke in February 1959* 
Dr. Cornelius P. Rhoads, Director of the Sloan-Kettering Institute 
for Cancer Research, was the victim of a heart attack in August. 
Dr. Dudley Jackson of San Antonio, Texas, who was one of the 
earliest and most energetic advocates of a National Cancer 
Institute, and long an ardent supporter of cancer research and 



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- 2 - 

control, died in July. Indeed, it will "be difficult, perhaps 
impossible, to replace these leaders. Such men of vision helped 
shape the pattern of cancer research as we know it today. 

Mr. Chairman, the research programs of the National 
Cancer Institute, again this year, reached an unprecedented level 
of operation which has been made possible by the steady increase 
in Congressional appropriations . We recognize that this growth 
carries with it the added responsibility to apply every appropriate 
means to finding a solution of the problem of malignant disease, 
whether through prevention, arrest, or cure. 

DEVELOPMENTS IN THE PAST DECADE 
Perhaps an effective way of introducing a discussion of 
the Institute's activities would be to look at some of the 
accomplishments in cancer research and control over the past decade, 
Within the last 10 years, the body of scientific knowledge relative 
to cancer has grown, not by dramatic leaps, but in a steady fashion. 
Ten years ago, there was relatively little basic knowledge about 
the nature of cancer. Seemingly unrelated investigations in 
biochemistry, bacteriology, genetics, and virology had not yet 
been linked by the realization that these studies pertained to the 
nucleic acid of the cell which affects cell characteristics and 
reproduction. Now that medical research has yeilded a wealth of 
information on the role of nucleic acid in the life and death of 



- 3 - 

cells , genetics, virology, radiology, environmental cancer research 
and numerous other lines of investigation are merging, and the 
whole field of cancer research is "becoming more unified. 

This synthesis of research has opened up new opportunities 
for advances in many fields including chemotherapy and virology, 
which I shall discuss elsewhere in this document. Suffice it to 
say here that the progress in cancer chemotherapy in the last 
decade is marked "by the development of a number of drugs for the 
temporary control of human cancer. In 1950, the average acute 
leukemia patient survived only a few months after diagnosis. 
Today, the average patient may live a year or more. And in 
virus-cancer research, new knowledge has led to the development 
of vaccines that will prevent certain viral tumors in animals. 
There is real hope that research may show that some forms of 
human cancer are caused by viruses and that these, too, might 
be prevented by vaccination. 

The cytologic test for cancer of the uterine cervix has 
been proved an effective case -finding technique, and its use can 
lead to the virtual elimination of mortality from this form of 
cancer. 

With the opening of the Clinical Center, the National 
Cancer Institute was able to relate closely the study of cancer 
in man and the more fundamental, supportive research at the 



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- k - 

laboratory level. This development is representative of a trend 
toward greater emphasis on the application of sound scientific 
methods in clinical cancer research throughout the Nation. 

Another achievement of major importance in the past decade 
is the accumulation, for the first time, of a comprehensive body 
of knowledge of the epidemiology of cancer. Prior to the 
collection of these data, much less was known of the incidence 
of cancer by age, sex, race, site, geographic region, etc. Today, 
a valuable body of knowledge exists that is being used to explore 
the relationship of environmental factors to the causation of 
malignant disease. 

Because the supply of highly trained scientists in this 
country is still far from adequate, the National Cancer Institute 
expanded its support of research fellows and, a few years ago, 
established a training grants program to assist qualified 
institutions in preparing scientists and physicians to enter the 
cancer field. Scientists trained in these programs have played 
an important part in expanding cancer research during the past 
ten years- -this increase in research has been one of the noteworthy 
developments of the decade . One measure of this increase in cancer 
research activity is the increase in appropriations to the National 
Cancer Institute which has risen from $20,000,000 to $91,000,000 
between the years 1951 and i960. 



- 5 - 

The progress made heralds further advances in the years to 
come. I should like now, Mr. Chairman, to mention a few examples 
of research findings reported "by National Cancer Institute staff 
scientists and grantees in the past year and then turn to a dis- 
cussion of the special research programs in which the Committee has 
expressed particular interest: virus research, diagnostic research, 
and cancer chemotherapy. 

EXAMPLES OF RECENT RESEARCH FINDINGS 

Institute staff scientists have developed a procedure for 
testing anticancer drugs in animals in a way that yields precise 
quantitatives information about their effectiveness. The agents 
are administered to mice that have far advanced leukemia and are 
only a few days from death. Drug effect is measured in terms of 
lengthened survival of treated animals over untreated controls. 
Using this technique, the investigators evaluated a series of 
derivatives of methotrexate, the widely used antileukemia drug. 
Two of the derivatives, 3'-bromo-5 ' chloroamethopterin and, 
3' ,5 '-dichloroamethopterin, produced survivals of 90 days, three 
to four times greater than those achieved with methotrexate. Some 
animals were still alive 6 months after treatment and were believed 
cured. Reinoculation of leukemic cells in these animals failed 
to produce the disease, suggesting that they may have "become immune. 
One of the two compounds, 3 ' ?5 '-dichloroamethopterin, has been 



- 6 - 

placed in preliminary clinical trial in the National Cancer 
Institute intramural research program and under the program of 
the Cancer Chemotherapy National Service Center. 

One of the continuing goals of clinical chemotherapy research 
is to find ways of enhancing the therapeutic effect of existing 
drugs. A group of Institute grantees has reported on studies of 
the isolation-perfusion technique for administering anticancer 
agents. Essentially the technique involves isolating the tumor- 
hearing area (arm, leg, pelvis, etc.) from the normal circulation 
stream and introducing into the area relatively high concentrations 
of anticancer drugs. Although there is great variation in response 
to isolation-perfusion chemotherapy, it appears that this technique 
may prove highly valuable in the treatment of certain forms of 
cancer. 

For the past several years, I have reported to the Committee 
on the chemotherapy of a rare form of uterine cancer Known as 
choriocarcinoma. As you know, this is one of the few instances 
in which treatment with a drug, in this case methotrexate, has 
produced complete remission in patients with far advanced, 
metastatic cancer. Our experience now indicates that approxi- 
mately one-third of choriocarcinoma patients who receive massive 
doses of methotrexate experience disappearance of all signs and 
symptoms of cancer. One such patient treated at the Clinical Center 



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has remained apparently free of disease for more than ^3 months. 
The scientists involved in this investigation now "believe that 
methotrexate should be considered the treatment of choice for 
patients with choriocarcinoma. 

Further studies with combination therapy of x-ray and the 
antibiotic , Actinomycin D, have demonstrated favorable responses 
in patients with certain cancers such as Wilms' tumor and Ewing's 
tumor. Simultaneous radiotherapy and chemotherapy in low dosage 
appeared to be as effective as higher doses of either component 
alone, and somewhat longer therapeutic effects were obtained with 
the combination therapy. 

A new alkylating agent, cyclophosphamide, is highly 
effective in prolonging the survival of mice with advanced 
leukemia. The new drug, developed and first tested in West Germany 
and marketed in the United States as Cytoxan, has been placed 
in preliminary clinical trial against leukemia and various solid 
tumors under the program of the Cancer Chemotherapy National 
Service Center and the intramural research program of the Institute. 

For the past several years, the incidence of stomach cancer 
in the United States has been downward. In contrast, cancer of 
the lung has been increasing. It is interesting to note that 
cancer of the female breast, the leading cause of death from 
cancer among women, remains relatively unchanged. Institute 



- 3 - 

scientists, in collaboration with investigators of the 
Connecticut State Department of Health, reported within the 
year that survival among breast cancer patients has remained 
stable for about a quarter of a century. This finding leads the 
scientists to the conclusion that any substantial improvement 
in this form of cancer is more likely to result from the develop- 
ment of new forms of treatment rather than from further modi- 
fications and refinements of existing methods. 

VIRUS RESEARCH 
Research on the possible relationship of viruses to human 
cancer has rapidly become one of the most active and provocative 
areas of the National Cancer Institute's program. Several months 
ago, a scientist in the Institute's Laboratory of Biology reported 
the discovery of a new virus-induced tumor that we believe is of 
particular importance. This fascinating study began with an 
investigation of some of the properties of Sarcoma 37 ;> an experi- 
mental mouse tumor. In the course of this work, the investigator 
prepared a cell-free extract of the tumor and injected it into 
healthy mice. The result was entirely unexpected. Within eight 
months, the injected mice developed leukemia of a type virtually 
indistinguishable from the spontaneous form of the disease in mice. 
Following this new lead, the scientist prepared fresh extracts 
from leukemic tissue of the animals that first developed the 



- 9 • 

disease and injected these into mice. After several of these 
so-called selective passages/ an extract was obtained that 
causes leukemia within 10 weeks in 100 percent of the mice 
injected on the first day of life. The leukemia-producing 
agent in the extract is a virus, which has been seen under the 
electron microscope. In contrast to other leukemic viruses 
affecting mice, this new agent elicits the disease in several 
different strains and is active in adult as well as newborn 
animals. None of the injected mice has developed any form of 
cancer other than leukemia. 

Discovery of this new virus leukemia is particularly 
important at first, because it provides additional information 
about the role of viruses in animal cancer, and second, and perhaps 
more important , because it may become an extremely valuable model 
test system for use in further research on the human virus-cancer 
question. 

I am glad to report that our grant -supported virus research 
is going very well. There are now in effect 110 grants for 
studies in this area, and their total value is nearly $4,000,000, 
which is about a twofold increase in the past year alone. Among 
the investigators who are participating in this expanded program 
are many virus experts who are entering the cancer field for the 
first time . 



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The phase of virus-cancer research into which we are now 
entering presents a number of problems and obstacles which 
necessitate some modifications in our attitude toward grants 
for virus research. For example, greater consideration is being 
given to long-term support of the scientist himself rather than 
to the specific virus research project he proposes to undertake, 
because of the complexity and difficulty of virus research, 
particularly in man. Support for some of these virus studies has 
been recommended for periods up to 10 years . We agree with our 
advisors that these attitudes and practices are decidedly 
important if virus-cancer research is to be pursued in the most 
wise and productive manner. 

The many and varied problems confronting scientists in 
the conduct and future course of research on the relationship of 
viruses to human cancer were discussed at a recent meeting in 
Rye, New York, held under the auspices of the American Cancer 
Society. It was attended by many of the Nation's leading in- 
vestigators in the virus-cancer field, most of whom are grantees 
of the National Cancer Institute. 

At first glance, it would appear relatively simple to 
establish the role of viruses in the production of human cancer. 
One would have only to find viruses in malignant tissue and then 
demonstrate that they had caused the disease . This is an extremely 



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- 11 - 

complicated task. Even though virus-like particles have been seen 
in electron microscope pictures of human leukemic tissue., scientists 
are still confronted with the extremely difficlt task of demonstra- 
ting whether a virus that may be isolated from human tumor tissue 
is indeed the causative agent. The fundamental problem lies in a 
lack of an established means of testing the carcinogenic effect of 
viruses on humans. Therefore, an important goal is the development 
of laboratory techniques that will attack the problem indirectly. 
We believe that significant progress has been made in the 
fundamental studies that are needed to equip us with knowledge to 
investigate the virus-cancer problem. For example, the number of 
laboratories where human cells are being grown in tissue culture 
has greatly increased in recent years, and this has facilitated the 
search for and study of carcinogenic viruses in human tissue. Other 
work is steadily expanding knowledge of the chemical and biological 
nature of viruses and their behavior within cells. The discussions 
at Rye indicated that some progress is being made in clarifying the 
biochemical association of viruses to the innermost constituents of 
the cell. This work is aimed at finding out how viruses might enter 
a cell and make it cancerous. Just how this might happen remains to be 
explained, but there is evidence, based on studies in bacteria, that 
a virus may entwine itself in the cell's genetic mechanism and so 
modify it that the cell begins to reproduce abnormally. Or, a virus 
may enter a cell, attach to itself some of the cell's genes, and transport 



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12 - 



them to a second cell, again causing an abnormal , malignant 
change. There is support for the suggestion that a dormant 
virus hidden within a cell may be activated by some external 
agent, such as x-rays, and thus start the process of malignant 
growth. 

Each of these possibilities and many others need to be 
thoroughly investigated in order to gain precise knowledge of 
the virus-cancer relationship. Scientists must learn much more 
than is now known about the so-called "model virus tumors," the 
role of immunity, the significance of other non- cancer producing 
viruses present, the effect of antibody formation, the influence 
of one virus upon another, and a host of other facts. 

Furthermore, adequate supplies of laboratory materials 
essential to research on the role of viruses in human cancer must 
be made available. Among these are "banks" of normal and malignant 
human tissue, several of which are now in operation, and uniform 
preparations of virus materials. The Institute, under guidance 
of the recently formed Viruses and Cancer Panel, has taken steps to 
establish two tissue-culture cell banks, which now make available 
to investigators cells of known properties. Selected cell strains 
will be kept for long periods in a frozen state to serve as 
reference materials. Tumor viruses and antisera against them will 
also be preserved in the same way. 



- 13 - 

What could medical science do if cancer were proved 
to be a virus disease? You will remember, I touched briefly 
on this question last year. At that time I suggested that it 
might be possible to develop a vaccine that would prevent man 
from developing cancer. We should consider, though, that it 
might take many years to determine the effectiveness of a human 
anticancer vaccine, were one developed. On the other hand, 
if acute leukemia, for example, were found to be a virus disease,. 
we would probably know within a few years whether a vaccine 
administered to babies was effective, because this form of 
cancer most often strikes young children. It should be pointed 
out that the isolation and identification of a cancer-producing 
virus may not lead to the quick development of a vaccine. 
Viruses differ in the properties that determine the ease 
with which they can be used in the preparation of vaccines. 
I reported last year that some success had been achieved in 
detecting antibodies against the polyoma virus and preventing 
tumors in hamsters following injection of the virus. On the 
other hand, attempts to detect antibodies against the mouse 
leukemia virus mentioned earlier have so far been unsuccessful. 

Moreover, the steadily growing body of knowledge of the 
oiochemistry of viruses and their effects upon cells may 
eventually permit the development of antiviral drugs. Laboratory 
studies have shown, for example, that a virus that infects 



t •-: 



- Ik - 

bacteria can induce the formation of an enzyme necessary for 
reproduction of the virus within the cell. A potent anti- 
tumor agent, 5-fluorouracil deoxyriboside, blocks this newly 
formed metabolic pathway by combining with the enzyme. Thus, 
the drug selectively attacks only the bacteria infected by 
virus. 

Additional virus research accomplishments within the 
year include : National Cancer Institute - Division of Biologies 
Standards studies showing that the polyoma virus is a single 
organism rather than' a group of viruses each of which induces 
malignancy at a specific site; immunization of female hamsters 
during pregnancy substantially reduces the incidence of tumors 
in offspring challenged at birth with polyoma virus; human cancer 
cells can be grown in a tissue culture medium free of blood serum 
and, therefore, also presumably free of certain virus inhibitors 
that may be present. An Institute grantee succeeded in growing 
human cancer in previously untreated laboratory animals by 
injecting the malignant cells into fetal rats a few days prior 
to birth. Because the fetal animals apparently lack natural 
resistance to foreign transplants, the cells were able to multiply 
and continued to grow after birth. If perfected, such a technique 
may be of value not only in human virus-cancer research, but in 
chemotherapy, and other areas of investigation. ■ 



- 15 - 

The implications of this work in viruses and cancer 
are literally "beyond imagination. Yet, it does not appear 
unreasonable to anticipate that research on the relationship 
of viruses to cancer may ultimately lead to a completely new 
and highly effective means of preventing or arresting the 
development of human malignant disease . I am glad to say that 
the National Cancer Institute is making an important contribution 
toward the accomplishment of this goal. 

DIAGNOSTIC RESEARCH 
At the appropriation hearings a year ago, I reported to 
the Committee that steps had been taken to initiate a program 
of intensive research to develop improved tests or other procedures 
for the detection of early cancer. As of December 1, 1959 > "ten 
contracts and several other direct cooperative projects were in 
effect. One aspect of the work in progress is biochemical studies 
to determine differences in the distribution of enzymes and other 
elements in the blood of cancer patients and other persons, in an 
attempt to identify some consistent characteristic of the blood 
of cancer patients that can be detected before overt symptoms 
appear. With essentially the same objective in view, other 
studies are attempting to develop the technique of fluorescent 
microscopy so that it can be used to detect early cancer. Research 
is continuing in an effort to assess the significance of malignant 



- 16 - 

cells in the peripheral blood of cancer patients. As yet, it 
is not clear what interpretation can be placed on the findings 
of malignant cells in the blood stream. 

We will continue to make use of the grants mechanism to 
provide support for fundamental studies in the area of cancer 
diagnosis, and we will utilize our contract authority for other 
studies that are best suited to this form of support. 

In addition to the diagnostic research program per se , 
a number of other developments in the area of cancer detection 
deserve special mention. 

Thanks largely to the work of the Field Investigations 
and Demonstrations Branch over the past several years, the 
cytologic test for detection of early cancer of the uterus has 
been established as a reliable procedure for detecting this 
form of cancer at a stage when it is virtually 100 percent 
curable. Further research in this area has been designed to 
obtain more complete cytological, epidemiological, clinical, 
and pathological information on uterine cancer. Significant 
information gained from these studies is being made available 
to operating programs for general application as new techniques 
are developed and proved effective. As reported previously, 
efforts are under way to devise methods of applying cytology 
to the detection of early, symptom-free cancer of other sites , 



- 17 - 

such as the colon, lung, stomach, urinary system, and prostate. 
Three such projects are in progress at this time: colon and 
large bowel cytology at Ohio State Medical School, Columbus, 
Ohio; lung cytology at the University of Texas, M. D. Anderson 
Tumor Clinic and Hospital, Houston, Texas; and gastric cytology 
at the Bowman-Gray School of Medicine, Winston-Salem, Worth 
Carolina. 

Another important aspect of our continuing cytologic 
research activity involves development of the cytoanalyzer . 
A large-scale, clinical trial of this instrument involving 
approximately 10,000 vaginal specimens is now in progress and 
is expected to complete the developmental work with the 
cytoanalyzer, so far as uterine cytology is concerned. It is 
anticipated that this field trial will he completed late in 
I960. 

CANCER CONTROL PROGRAM 
In fiscal year i960, the Cancer Control Branch of the 
Bureau of State Services, U. S. Public Health Service, will 
comp3.ete its first year of operation. This program is conducted 
under the technical guidance of the Director of the National 
Cancer Institute. The program is devoted to strengthening the 
Nation's cancer prevention and control efforts, with the State 
health departments as a pivot around which these activities will 
be developed. 



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- 18 - 

A series of regional meetings is being held with represent- 
atives of medical groups from "both private practice and public 
health. These discussions have helped identify opportunities and 
obstacles in extending community cancer control work and have 
contributed to the creation of a national effort among the various 
professional groups with interests in this program. 

One of the first goals of a program of this kind is to 
assess the present state of cancer control activities at the 
local level. Reports on the current conduct of State health 
department plans and projects, the nature and extent of 
facilities, and the availability of nursing education courses 
in cancer control are being prepared for publication. 

Naturally, the success of a cancer control program depends 
largely on the communication of useful information about the 
disease to the general public . To explore and evaluate ways of 
reaching different population groups and to enlist their cooper- 
ation in uterine cytology screening programs, pilot projects 
are being carried out in a number of cities throughout the 
country. In this way, information is being gathered on 
successful and unsuccessful methods of encouraging women of 
differing backgrounds to avail themselves of the cytologic test 
for uterine cancer. These projects also provide training for 
medical, nursing, and related personnel in current cancer 
detection techniques. 



:;>_ 



- 19 - 

An important component of the Cancer Control Program is 
the Cancer Community Demonstration Project Grant Program, which 
is intended to help local communities to apply proven control 
measures. Emphasis is being concentrated on developing projects 
in prevention, public and professional education, early diagnosis, 
case reporting, and rehabilitation. Professional and voluntary 
agencies, as well as State and local health departments and 
community hospitals, are "being encouraged to participate in 
this work. Applications for project grants are reviewed "by the 
appropriate State Health officer, by the Advisory Committee to 
the Control Program, which includes nonfederal consultants in 
the medical sciences, public health administration and related 
fields; and by the National Advisory Cancer Council. It is 
anticipated that 30 to kO such projects will be supported 
during the 1961 fiscal year in communities throughout the 
country. 

CANCER CHEMDTHERAPY PROGRAM 
The program of the Cancer Chemotherapy National Service 
Center is now in its fifth year of operation and a considerable 
body of information has accumulated which is now permitting 
comprehensive reviews and analyses not previously possible. 
They are being undertaken to insure that the chemotherapy activity 
maintains its present well-rounded mode of operation and that no 
major areas are being inappropriately neglected or overemphasized. 



- 20 - 

Synthetic chemicals and antibiotic materials are "being 
screened at the rate of about 40,000 a year. These are 
supplied by contractors engaged in synthesis work, by ''prep lab" 
contractors who furnish commercially unobtainable compounds, and 
by universities, research institutions, and industrial firms. 
During the present calendar year (i960), an additional 500 
synthetic compounds per month will be screened in tissue culture 
rather than in the conventional mouse tumor system since 
insufficient quantities are available for the primary animal 
screen system. In addition, the screening of plant materials will 
receive increased attention in the coming year. This is a new 
source of materials and is of interest because of activity 
already found in several plant products. 

Handling of the large, and constantly growing, volume of 
information created by the primary screening operation was made 
largely automatic within the year by the activation of a new 
electronic data processing machine. This will make possible the 
rapid return of information on screening results to the suppliers 
of test materials. 

In order to achieve the high level of screening activity 
commensurate with the supply of new materials, it has been 
necessary to increase production of inbred animals. Since the 
inception of the chemotherapy program x the supply of animals has 



- 21 - 
risen frcm a level of 100,000 per year to more than 1,500,000 
per year. Standards to protect the quality of laboratory 
animal production and effective methods to control disease 
among such animals have been established. 

The clinical trials portion of the Service Center's program 
has attained an unprecedented level of operation in terms of the 
numbers of studies, investigators, new agents, and patients in- 
volved. At present there are 17 clinical groups participating 
in the program in ikj hospitals, including public and private 
institutions, Veterans Administration hospitals, and the Clinical 
Center of the National Institutes of Health. 

There are now 109 drugs in various stages of clinical 
evaluation in studies involving some 7>700 patients. These include 
53 steroids and hormones, 22 alkylating agents, 8 antibiotics, 

16 antimetabolites, and 10 miscellaneous agents. Plans are now 
being made to accelerate the clinical evaluation of drugs. During 
the 1959 calendar year, preclinical evaluation was completed on 10 
new agents that appear to warrant testing in man. At present, 

17 other new compounds are in various stages of preclinical pharma- 
cology and should be available for clinical trial within the next 
six to twelve months . : 

Perhaps the chief problem in the chemotherapy area that 
awaits solution is the lack of satisfactory correlation between 



the results of drug testing .in animals and clinical trials. 
This point was strongly emphasized at the first Conference 
on Experimental Clinical Cancer Chemotherapy, which was held 
recently in Washington under the sponsorship of the Service 
Center. Some 63O clinicians and other scientists participating 
in the national chemotherapy program attended the two -day 
conference and heard reports on the status of the cooperative 
clinical trials and other aspects of the program. The view 
was expressed by many speakers that better statistical 
correlation between animal and clinical studies will be 
possible as more clinical experience is gained with the drugs 
now available, and as this experience is analyzed by precise 
statistical methods. Another approach to this problem which 
is under careful consideration is the addition of more animal 
tumors to the primary screening process. The objective here 
would be to attempt to relate to human tumors the response 00 
chemotherapy of particular animal tumors. Some initial work 
along thj.s line has been encouraging/, and we may hope that 
further efforts will produce a screening system that enables 
excellent prediction of drug action in man. 

The bulk of the program administered by the Service 
Center, apart from clinical trials, is being carried out under 
contracts with industry, non-manufacturing research insti- 



- 23 - 

tutionsj, colleges, and universities. There are 108 chemotherapy 
contracts in effect and many of the Nation' s leading 
pharmaceutical firms are actively engaged in contractual 
chemotherapy research. 

The chemotherapy program has encouraged more scientists 
to undertake the study of cancer than might have done so other- 
wise, and has achieved a more universal definition of the cancer 
problem and approaches toward its solution. The program has 
provided training for hundreds of scientists and physicians 
not only in cancer research hut in the basic sciences generally. 
It has contributed to fundamental chemistry through the develop- 
ment of new and unusual methods of chemical synthesis and the 
production of large quantities of unique compounds. It has led 
to the organization of a national, standardized system for 
reporting end results in cancer, thus providing a base line 
of the effect of treatment in more than 50,000 patients a year. 
The clinical trials are introducing sound research methodology 
in the clinic to many young physicians who otherwise would 
not have received such research training. These are only a 
few of the byproducts of the national cancer chemotherapy 
research program. 

The Cancer Chemotherapy Program has and is being studied 
to determine whether steps can be taken to improve it and the 



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chances for finding fully effective anti-cancer agents. We 
know that our screening techniques fall far short of the ideal. 
Yet most of those who know this field and program believe that 
the substantial investment in this program is warranted even 
though no -one can predict that the cure for cancer will come 
from the largely empirical approach which characterizes this 
program. 

TRAINING 
Dr. Shannon has discussed the importance of training 
programs to medical research progress. Those of us in cancer 
research are convinced that training must continue at a high 
level in the scientific disciplines concerned with the life 
sciences, for the great majority of these are required for 
cancer research. In addition, the training programs supported 
by the National Cancer Institute concentrates on cancer as a 
specialized problem in itself, and encourages competent 
scientists to make a career of cancer research. 

Dissemination of information continues to be a constant 
and burdensome problem affecting virtually every branch of 
scientific inquiry. Delay in publishing reports in the scientific 
literature is a major problem. Because of such delays, scientists 



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- 25 - 

may embark on carefully planned research projects only to find 
too late that other investigators have already covered the 
ground. One step taken to shorten the lag in publication of 
papers in the cancer field was the conversion of the Journal 
of the National Cancer Institute from a bi-monthly to a monthly 
publication. Now the Journal is being expanded further from 
2,1+00 to 3,000 pages per year. Even so, it is estimated that 
there will still be substantial delays in publishing worthwhile 
reports. To minimize these delays, reports of seminars and 
review papers of considerable length are to be published 
separately as monographs . 

We are continuing to utilize every available opportunity 
to improve and increase cancer research internationally. Many 
of our staff scientists have traveled to foreign nations to 
attend scientific meetings and exchange information with cancer 
investigators in other lands. Numerous visiting scientists 
have come to Bethesda to work in our laboratory and clinical 
facilities, to learn from us, and to give us the benefit of 
their experience. 

Of particular interest and importance this year were 
two international conferences on the evaluation of end results 
in the treatment of cancer. Scientists from England, Denmark, 
Finland, France, Norway, Russia, and the United States met with 



- 26 - 

members of the National Cancer Institute staff tc discuss 
plans for cooperative studies on end results, epidemiology, 
and incidence of cancer in various population groups through- 
out the world. A program of comparisons of end results in 
cancer is being planned fo? the Eighth International Cancer 
Congress, to be held in Moscow in 1962. Such comparisons 
should facilitate the application throughout the world of 
techniques found superior by workers in one country. Plans 
are being completed for the Fourth National Cancer Conference, 
which is held every four years under the auspices of the 
National Cancer Institute and the American Cancer Society. 
The meeting will be held in September I960 in Minneapolis 
and will be oriented primarily to the interests of clinicians. 
Outstanding authorities will discuss such topics as causation, 
control, and treatment of cancer under the general theme, 
"Changing Concepts Concerning Cancer. " 

CONCLUSION 
In conclusion, Mr. Chairman, the appropriation request 
for 1961 is a total of £88,869,000 as compared with the 
anticipated obligations in I960 of $87,757,000. This 
allowance for 1961 will provide for the continuation of I960 
program levels in all activities and will permit some increase 
in grants for research projects and minor increases in the 



- 27 - 

direct research activities of this Institute. This request 

for 1961 is distributed among program activities as follows: 

Grants : 

Research projects #35,941,000 

Research fellowships 1,912,000 

Training 7,055,000 

State control programs 2,250,000 

Community demonstration projects 1.500,000 

Total grants 48,653,000 

Direct Operation s; 

Research 12,395,000 

Review and approval 1,032,000 

Professional and technical assistance - 5,217,000 

Chemotherapy contracts 21,145,000 

Administration 422,000 

Total direct operations 40,211,000 



Total appropriation 88,869,000 

Under the budget we can increase our investment in 
research projects by f. 578, 000. An additional $45,000 will 
permit payment of full indirect costs on research projects awarded 
on and after January 1, 1961. It also provides for an increase 

of $300,000 in direct research activities. These additional 



- 28 - 

funds would be used for relocating our tissue preparation 
laboratory now housed in a temporary building which is to 
be torn down upon the completion of the Office Building; for 
expanding radiation studies, and for publication of the 
increased volume of scientific information.. Other changes 
in the budget relate to mandatory items and increases in 
reimbursement to the management fund and to decreases for 
non-recurring items. The net result ia an increase of 
$1,112,000 in obligations over i960 and a decrease in the 
total appropriation of $2,388,000. 

Now, Mr. Chairman, I shall be happy to answer any 
questions or aid in further discussion. 



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SUMMARY OF OPENING STATEMENT 

by 

Director, National Institute of Mental Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"Mental Health Activities" 



Mr. Chairman and Members of the Committee: 

During the past four years there has been marked expansion 
in all of the Institute's programs and many important new ways 
have been developed to help meet the challenge of mental health 
problems. During these years, the resident populations in the 
public mental hospitals have steadily declined. However, the 
number of admissions to these hospitals is still rising and, 
despite many favorable developments, the public health problems 
posed by mental and emotional disorders are still large and 
pressing. To help cope with these problems, the Institute has 
employed a dual approach in each of its major programs — attempting 
to find better ways of treating mental and emotional disorders 
which have already developed, and also attempting to develop 
effective preventive measures. 

Mental health project grants, grants in psychopharmacology, 
program grants, and career investigator grants have significantly 
enlarged the scope of research supported by the Institute. More 
emphasis has been placed on developmental grants in such important 
areas as juvenile delinquency, alcoholism, school mental health, 



- 2 - 

and mental retardation. Biological and social scientists have 
become increasingly interested in doing mental health research 
and many other new types of investigators are being drawn into 
work in this field. 

The Institute's intramural research work has likewise been 
broadened during the past few years. The Clinical Neuropharmacology 
Research Center located at Saint Elizabeths Hospital permits the 
Institute to study large populations of patients and to test 
therapeutic measures in a public mental hospital setting. The 
Institute is doing work on normal child development, patterns of 
family living, psychosomatic mechanisms, and biological aspects of 
schizophrenia. Other important areas of investigation include 
basic metabolic studies, intensive investigation of areas of the 
brain which control important aspects of human behavior, and 
fundamental studies of the chemistry of the body utilizing psycho- 
pharmacological substances as research tools. 

During the past year, important progress was made in research 
which attempts to establish causal relationships between biochemical 
processes and mental disorders. Research done under the auspices 
of the National Institute of Mental Health has pioneered in the 
establishment of better criteria on which to base such studies. 
The functions of various parts of the brain are being mapped by 
Institute grantees and for the first time during the past year 
support has been provided for a long-term program of combined 



- 3 - 

behavioral, anatomical, and neurophysiological studies in "split- 
brain animals." New biochemical methods are being used to measure 
emotional aspects of behavior and the Institute is supporting 
several studies on hereditary aspects of mental illness. 

The scope of the training grants program has also widened 
considerably during the last several years, and support for 
training has been extended to the 1 asic biological, behavioral, 
and social sciences, as well as to more varied areas of psychology, 
psychiatry, nursing, and social work. There has been an increase 
in support of training for research as well as for clinical work. 

During the past year support of research training was 
broadened to include all four mental health disciplines. Also 
a large proportion of awards for research training in the 
biological sciences placed considerable emphasis on psychopharma- 
cology. The Institute's psychiatric training program for general 
practitioners was received enthusiastically by the medical pro- 
fession. This training activity is especially important since 
it is estimated that 90 percent of all psychiatric problems 
receiving medical attention are handled by the family physician. 
During the past year increased support was also given for 
psychiatric training in medical schools, nurse training centers, 
and graduate schools of social work. 

The technical and professional assistance provided by 
Institute staff and the financial help of Federal grants-in-aid 
have stimulated the development of more adequate State mental health 



- k - 

programs. Technical assistance projects have been utilized by 
the Institute to help States strengthen their community mental 
health programs. Broad community-based programs are beginning 
to develop and there is greater recognition, on the part of 
leaders in education, industry, and other important segments of 
the community, of their responsibility for mental health work. 

The Institute's activities in the field of alcoholism 
were markedly expanded during the past year. The five-year grant 
to the North American Association on Alcoholism Programs will open 
the way for a reexamination of the entire problem of alcoholism 
and permit a unified and impartial approach to this urgent and 
costly problem. 

At the request of Congress, the Institute, in collaboration 
with the Children's Bureau, has conducted a study of the problem of 
juvenile delinquency and is preparing a report which attempts to 
answer the question: What can and should be done in the field of 
juvenile delinquency? 

The report includes both substantive and fiscal proposals 
for action. In the mental health project grants program, which 
supports studies aimed at developing new and improved methods 
for the care, treatment, and rehabilitation of the mentally ill, 
special consideration has been given to projects which impinge 
on critical problem areas such as schizophrenia, alcoholism, 
juvenile delinquency, mental retardation, and aging. 



- 5 - 
The Institute's Psychopharmacology Service Center has helped 
to stimulate research by working with and providing technical and 
professional assistance to individual investigators and small 
groups of researchers focusing on specialized problems. The 
effectiveness of these efforts is evidenced by the increased amount 
of psychopharmacological research. During the past year, a con- 
tract was awarded to support work on the synthesis of certain indole 
derivatives to be used in basic research. Work is proceeding in 
three major areas: (1) evaluation of the clinical efficacy of 
drugs in treating psychiatric conditions; (2) development of better 
methods for testing drugs at the preclinical level; and (3) inten- 
sive study of the biological mechanisms through which known psycho- 
active drugs produce their effects. 

Conclusion 
To continue the vital work of the Institute and consolidate 
the gains made during the past year, the appropriation request for 
1961 is a total of $67,563*000. This compares with the appropria- 
tion of $68,090,000 for i960. This allowance for I96I will provide 
for the continuation of i960 program levels in all activities. An 
adjustment downward of $3,850,000 reflects the nonrecurring adjust- 
ment of project period starting dates of training grants. An 
increase of $3,208,000 will be available for additional support of 
research grants. 



- 6 - 
The request for 1961 is distributed among program 
activities as follows^ 

Research projects $26,690,000 

Research fellowships 1,996,000 

Training grants 22,356,000 

State control programs 5*000,000 

Research 7,697,000 

Review and approval of grants 1,293,000 

Training activities 100,000 

Professional and technical assistance .. 1,926,000 

Administration 505,000 

Total $67,563,000 



OPENING STATEMENT 

by 
Director, National Institute of Mental Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 

"Mental Health Activities , Pablic Health Service" 



Progress in the field of mental health has proceeded at an 
accelerated pace during the past 3 or k years. Since fiscal year 
1957 j there has been a markedly expanded program of research, 
training, consultation, and other developmental activities in 
mental health. These years have also seen important new trends 
in the ways in which the National Institute of Mental Health has 
organized its programs to help meet the challenges and the many 
unsolved problems of mental health and mental illness. I should 
first like to address myself to the developments during these years. 

New Trends and Program Developments 
Research Grants 

New type s of progrs-ms have been made possibl e. The kinds 
of programs and activities supported by research grant funds have 
increased significantly beyond individual basic and clinical research 
projects. The Mental Health Project Grants and grants in psycho- 
pharmacology make possible a broad attack on problems of care, 
treatment, and rehabilitation of the mentally ill, and have stimu- 
lated evaluative studies of drug effectiveness. Program grants 



- 2 - 
permit teams of highly competent investigators a greater degree 
of freedom in;. -pur suing a variety of important". 'broad studies. 
Career investigator grants have helped fill the need for 
sophisticated psychiatric research personnel. These developments 
have done much to enlist the collaboration of research centers in 
new areas of particular concern to the mental health field. The 
support of individual projects has not suffered as a result of 
these developments. The increased appropriations during the past 
5 years have made the new developments possible concurrently with 
the normal growth in research organized by specific projects. 

More em phasis has been possible on developmental grants in 
areas of special public concern . The Institute has been enabled to 
work in close collaboration with several universities, mental 
hospitals, and other groups on large-scale studies to explore such 
areas as psychiatric rehabilitation, mental deficiency, juvenile 
delinquency, aging, alcoholism, and mental health in schools and 
in industry. These activities define new problems for research as 
well as new emphases in mental health programs, and result in 
generally increased mental health activity. The Mental Health 
Project Grants have encouraged the improvement of programs for the 
mentally ill through a variety of projects, including demonstrations, 
research, and evaluation studies. These grants have acted as a 
catalyst for such programs, increasing the interest and vigor of 
the staffs, enabling them to retain a higher level of personnel, 



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and fostering closer relations between mental hospitals and 
universities. Grants in peychopharmacology have made possible a 
more orderly development in a field of great promise. 

The Institute has also been able to provide funds for 
supporting activities, such as research conferences, abstracting 
services, development of regional cooperation through such agencies 
as the Western Interstate Commission on Higher Education and the 
Southern Regional Education Board and assistance to organizations 
like the American Association for Mental Deficiency and the National 
Association for Retarded Children so that they can provide the 
necessary leadership to professional workers in key mental health 
problem areas . 

The horizons of research in mental health have been widene d. 
There has been a marked increase in interest in research in mental 
health in the biological and social sciences. In addition, leaders 
in the fields of education, industry, public health, welfare, and 
vocational rehabilitation are beginning to recognize the importance 
of mental health considerations in their programs and are welcoming 
pilot studies. These developments have occurred concurrently with 
the steady pattern of growth of research in psychiatry, psychology, 
and the other behavioral sciences, and point toward a further 
broadening of research in mental health in the future. 

New groups are becoming involved in research . All of these 
changes have resulted in drawing new types of workers into mental 



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health research. Younger investigators who have done research as 
graduate students, or as young faculty members worked on grants under 
the direction of a senior investigator, are now applying for and 
receiving grants of their own. More social scientists and biologists 
are applying for and receiving grants. Social workers, nurses, 
vocational rehabilitation personnel, and other service professions are 
becoming interested in and are doing more research. Thus there is a 
growing manpower pool available for research in areas of increasing 
public interest and concern. 
Training Grants 

The areas of support have been broadened . High priority 
initially was given to training in the clinical areas of psychiatry, 
psychology, social work, and nursing, because of acute shortages of 
these personnel. But a need also was recognized for training in other 
areas. Increased appropriations have made it possible to support 
training in a broader range within psychology and social work. Basic 
biological and social sciences, and undergraduate psychiatry and 
nursing have been added to the program of support. A new program 
developed for training general practitioners has received a markedly 
favorable response from the medical profession. These developments 
help to meet the increasingly recognized needs for people with mental 
health orientation who have the widely varied skills required for 
professional work in such fields as family life, child development, 
institutional management, and community interaction. They go beyond 



- 5 - 
planning to meet the needs for early treatment and aim at the emergence 
of a "broad preventive program. Specialists in the biological and 
behavioral sciences are becoming a regular part of the faculties of 
medical schools , usually working closely with the departments of 
psychiatry. 

Clinical training in the core mental health professio n? h '3S_ 
also i nc rea sed. The needs for training clinicians to deal with the 
problems of those who become mentally ill or seriously disturbed 
emotionally have not lessened. By 1957 "the training center had 
reached a point where the potential was available for a marked 
expansion in the training program, including significant increases in 
traineeships as well as expanded teaching staff. Since that time, 
increased appropriations have made it possible to take advantage of 
this potential. 

There has been an increase in training for research . The 
expanded spectrum of research in mental health has required a parallel 
increase in training. New programs are being supported in research 
training in the four core disciplines and in various biological and 
social sciences of relevance to mental health. The number of research 
fellowships has markedly increased, both for predoctoral and for 
special advanced training. 

Increases in staff have enabled more effective collaboration 
b etween the Institute and the training centers , Training programs must 
be carefully planned on a long-term basis. Primary responsibility for 



-!•': 



- 6 - 
such planning lies, of course, with the training centers themselves, 
but they welcome the consultation of training specialists from the 
National Institute of Mental Health. These specialists also provide 
analyses useful for maintaining balance in meeting needs for training, 
research, and service. 
Community Services 

Broad community -based programs are beginning to develop . Clinics 
are becoming part of such programs and are providing consultation 
services as well as individual treatment for patients. Mental hospital 
personnel are beginning to collaborate with agencies in the community. 

Recognition of responsibilities for mental health has broadened . 
A recent survey of public health personnel indicated that mental health 
was considered to be the most important problem area. Responsibilities 
are being decentralized. A greater awareness has developed of the 
importance of preventive services and of aftercare for the mentally 
ill. 

Technical knowledge is growing in relation to special problem 
areas . Technical Assistance Projects, in collaboration with the States, 
are helping to develop better, mental health programs in such areas as 
school and industrial mental health, alcoholism, and aging. 

A ll States are benefited . In some States virtually no mental 
health services existed until the last decade. Increases in grants- 
in-aid have enabled these States to make important beginnings. 



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Increase in staff ha s provided more effective demonstrations 
and consulta tion. The Institute's Mental Health Study Center in 
Prince Georges County, Maryland, has pioneered in the development of 
a public health approach to problems of alcoholism. A local hospital 
and an outpatient clinic are collaborating with private physicians 
in case -findings, services to affected families, and rehabilitation of 
alcoholics. Increased staff in the Regional Offices has made consul- 
tation possible in relation to new experimental programs. The 
central office is able to do a more effective job of program analysis 
and of consultation on evaluative studies. 
Biometrics 

Modest increases in the Institute's biometrics staff have 
permitted expansions and improvements in the important field of 
reporting basic data concerning the incidence, prevalence, and 
treatment of mental and emotional disorders. Consultation service 
has been given to l6 States to improve their reporting systems. The 
Model Reporting Area for mental hospitals has increased from 18 to 
22 States since 1957. The hospitals in these States provide care 
for 75 percent of the patients in State and County mental hospitals 
in the United States on any one day. These 22 States spend approxi- 
mately $650 million annually for the care and treatment of patients 
in their State and County mental hospitals; this represents "J6 per- 
cent of the total spent for all State and County mental hospitals in 
the United States. The number of clinics reporting data relating to 



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- 8 - 
patients has increased from U00 to approximately 1,000. The 
biometrics staff has initiated a program in one State, on a pilot 
basis, of reporting data concerning patients from all facilities 
providing psychiatric care in the community. The staff has 
collaborated with staffs of the American Psychiatric Association 
and the World Health Organization in revisions and development of 
systems of statistical classification of mental disorders. 
^■^d^rjr-" 1 - Clin leal Investi gation s 

The establishment of the Institute's Clinical Neuropharma- 
cology Research Center, located at Saint Elizabeths Hospital, has 
been a ma,}or development. The Center provides the opportunity to 
study large patient populations and to test new and old methods of 
therapy in a public mental hospital setting. A group of laboratory 
scientists has been brought into direct contact with problems of 
mental disorders, and this has influenced the formulation of some 
of their research problems. The program of Clinical Investigations 
generally has expanded to include studies of normal child development, 
of successful coping behavior in adolescents, and of patterns of 
family living, thus providing control populations in which those 
factors responsible for adaptive and maladaptive behavior may be 
identified. In keeping with the interdisciplinary character of the 
Institute's research program, considerable emphasis is also being 
placed on the biological aspects of behavior, and of schizophrenia 
in particular. The mechanisms by which emotions influence somatic 



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- 9 - 
responses are being studied, and knowledge is being acquired 
about tbe way in which amino acids and certain amines of relevance 
to the brain, such as adrenaline, are handled in normal and 
schizophrenic individuals. 
Intramural Basic Resear ch 

A new resource, a small research greenhouse, has made 
possible the initiation of research, using plants, on a number of 
important problems, particularly the biosynthesis of alkaloids. An 
important discovery already has been made that methylation processes 
important to activation and inactivation of many pharmacological 
agents take place by way of the same biochemical steps in plants 
and single -celled organisms as in higher mammals, including man. 
This opens the way to studies of certain key metabolic processes 
starting with plants, where control of growth, harvesting, and bio- 
chemical separation of products is simpler than with animals. Easic 
studies are continuing on protein synthesis, on the biochemical 
mechanisms underlying the catalytic action of certain large mole- 
cules, and on the way in which nucleic acids may order the sequence 
of amino acids in proteins and hence transmit genetic information. 

Analyses of the circuitry of the brain have revealed separate 
locations for two major life principles: one relating to survival of 
the individual, located in the temporal lobe, and the other relating 
to the preservation of the species, located in a midline region of 
the forebrain. At present, regions of sexual representation in the 



■<C£j8 



- 10 - 

forebrain are "being studied. Important advances have "been made 
toward identifying brain mechanisms relating to consciousness and 
alertness as they are differentially affected by narcotic, psycho- 
tomimetic, and tranquilizing agents. A significant new finding 
about the action of the thyroid hormone on protein synthesis may 
explain many of this hormone's important functions and the mechanism 
whereby its lack causes cretinism, a state of mental and physical 
retardation. 

The Current Status 
Despite these developments during the last several years, 
the major task still lies ahead. Although resident mental hospital 
populations declined during 1959 for the fourth consecutive year, 
there still were over half a million patients in the 277 public 
mental hospitals in the United States at the end of fiscal year 1959- 
The annual tax bill for the care and treatment of the mentally ill 
still exceeds $3 billion. And though the number of discharges from 
mental hospitals is increasing, so is the total number of admissions. 
Admissions to mental hospitals increased by 6.5 percent between 195^ 
and 1959; and this was on top of a 7-7 percent increase the year 
before. Recent revaluations of the mental health manpower situation, 
show that although the number of trained persons has increased 
significantly, the demands for such personnel have increased at an 
even greater rate. Much valuable progress is being made in the wide- 
spread areas of mental health research, many answers are still unknown, 
and true preventive work in mental health is still in its developmental 
stage . 



«Sf 



- 11 - 

Pr ogress in the Past Year 
Important progress x*as made during the past year in the 
various Institute programs * There were new research findings, 
increases in mental health training, expanded community services 
activities, and significant advances in special areas such as 
psychopharmacology, juvenile delinquency, and alcoholism. Each of 
the Institute's major programs has included both activities designed 
to develop more effective methods of treating mental and emotional 
disorders and activities which attempt to find ways of preventing 
such disorders. Therapy and prevention have been the dual goals in 
research, in training, in community services, and in the work on 
special mental health problem areas. Basic laboratory and clinical 
research in the biological, psychological, and sociological sciences 
seeks to develop knowledge which will explain the factors controlling 
mental health and mental illness. Clinical studies, applied research, 
and special projects and demonstrations aim at developing more effec- 
tive ways of treating mental and emotional disorders and of bringing 
better and prompter care to all types of individuals who need mental 
health services. The Institute supports training for a very broad 
range of professional personnel who can contribute to therapeutic 
and/or preventive work in the field of mental health. The work in 
community services also includes activities designed to develop and 
strengthen State and local programs devoted to care and treatment and 
programs aimed at building sound mental health. 



X>J 



- 12 - 

Research 

Recently, research has suggested that some forms of mental 
illness may he related to "biochemical processes in the "brain and 
nervous system. Establishing definite causal relationships between 
changes in brain functions and the occurrence of mental illness is a 
complicated task since the brain is the most complex structural 
organization known to man. It is made up of a great many separate 
subsystems, each with its own neurophysiological and biochemical 
patterns of organization. 

One approach to this problem lies in the search for possible 
psychotoxic substances that may occur in the blood or urine of 
patients suffering from mental illness. Many pitfalls plague this 
area of research, however, and all to frequently exciting early 
reports of significant biochemical differences between normal and 
psychotic persons fail to stand up under adequately controlled repli- 
cation. National Institute of Mental Health grantees and scientists 
from the Institute's own research programs have contributed important 
new knowledge in this field and have demonstrated the importance of 
rigorous dietary controls in biochemical studies on mental illness. 
Institute scientists engaged in a multidisciplinary program of 
biological studies in schizophrenia have spearheaded a growing 
awareness of the sources of error in a more critical approach to the 
biological factors in schizophrenia. Many of their concepts are 
becoming widely used in the prosecution of similar undertaking here 



- 13 - 

and abroad. For example, the psychiatric, genetic, social, and 
medical criteria for the selection of schizophrenic patients in 
biological studies of the disease established by Institute scien- 
tists have constituted a model for studies elsewhere. 

Another major area of research is on the structure of the 
brain itself. A large number of Institute grantees are conducting 
studies on the behavioral role of some of the brain subsystems. The 
functions of various parts of the brain are being mapped with the 
aid of new devices which permit electrical and chemical stimulation 
to be applied with increasing accuracy to specific parts of the brain. 
Institute support has been provided for the first time this year for 
a long-term program of combined behavioral, anatomical, and neuro- 
physiological studies in "'split -bra in" animals in which the cerebral 
interhemispherical connections are interrupted. This technique pro- 
vides a unique opportunity for evaluating the extent of transfer of 
stored information from one hemisphere of the brain to the other and 
for isolating certain brain pathways and mechanisms. It is expected 
that this program will contribute significantly to our knowledge of 
the underlying mechanisms of memory and learning. 

Clinical investigators at the National Institute of Mental 
Health are conducting studies of emotional aspects of behavior, and 
are using new biochemical methods for the microanalytical assay of 
blood hormone concentrates which make it possible to confirm or deny 
clinical impressions with more precise measurements . Recent findings 



- lis- - 
have emphasized the likelihood of some predisposition on the part 
of certain individuals to specific psychosomatic dysfunction. Inves- 
tigators supported by Institute grants are conducting research on 
the specificity of physiological reaction to stress and on the 
patterns of autonomic responses in psychosomatic disorders. The 
Institute is also supporting several studies on the hereditary 
aspects of mental illness. These investigations suggest that 
heredity plays an important role in some types of psychosis and in 
some forms of mental retardation. However, the genetics of behavior 
is still a largely unexplored field, and the hereditary basis of 
normal behavior and of specific mental disorders requires much more 
exploration. 
T raining 

As of 1959, programs were being supported for research training 
of psychologists and for the interdisciplinary training of psychia- 
trists and of biological and social scientists. In I960 support of 
research training was broadened to include all four mental health 
disciplines => In addition, support for research training in the 
biological and social sciences was extended. The greatest proportion 
of awards in I960 for research training in the biological 
sciences included considerable emphasis on psychopharmacology. 
This has been especially appropriate because of the acute shortage 
of Qualified research workers in this area. 



'•• -VI 



-it ic 



- 15 - 

In September 1958 » "the first official announcements describ- 
ing the Institute's psychiatric training program for general 
practitioners were issued. Within six months the total funds 
allocated for the program were obligated,, Under this program, the 
Institute provides support for general practitioners who are taking 
psychiatric residency training, and for postgraduate psychiatric 
training courses for general practitioners o A total of $2,300,000 
will be expended for this purpose in I960. The importance of these 
training activities is highlighted by a recent estimate that at 
least 90 percent of all psychiatric problems receiving medical atten- 
tion are handled in the office of the family physician. 

Support was initiated in I960 for the development in medical 
schools of training programs leading to the integration of the 
behavioral sciences into the education of the modern physician, thus 
giving him a broader scientific basis for understanding human behavior. 
Research models are needed in the behavioral sciences which will be 
as meaningful and strong in their impact on medical education as 
those presently available for teaching in existent basic science 
departments and in other branches of medicine. 

Undergraduate psychiatry grants, awarded since 1950 » have 
enabled departments of psychiatry in all major medical schools and 
schools of osteopathy to improve and expand their undergraduate instruc- 
tion in psychiatry. In a number of medical schools, these funds have 
been a major factor in the establishment of new departments of 



- 16 - 

psychiatry and in the expansion of needed teaching staff. One new 
grant of $25,000 to be awarded in i960 brings the total to 88 medical 
schools and schools of osteopathy each receiving up to a maximum of 
$25,000 for teaching costso 

A portion of the funds provided in i960 was used to expand 
existing graduate teaching grants in a limited number of nurse 
training centers. During the past year, there was also an expansion 
of support in both clinical psychology training centers and centers 
for research training in fields of psychology relevant to mental 
health. A small experimental program of research training for under- 
graduate students was initiated in the summer of 1959 to offer extra- 
curricular research experience for the early development of research 
interests in undergraduate students majoring in psychology. 

The Institute now makes grants to 51 of the 56 graduate schools 
of social work in the United States. Fifty of the 51 received grants 
in psychiatric social work, and 1? of them received grants in school 
social work. For the first time, grants were awarded to training 
programs in the fields of aging, family and child welfare, correc- 
tions, and community planning. This represents the first application 
of funds for training social work personnel for work in these preven- 
tive mental health programs. 

A significant number of behavioral and social scientists are 
receiving research training in fields important to mental health 
(psychology, psychiatry, sociology, and anthropology) through the 



O'l J 



- 17 - 

research fellowships program. Support is being given to promising 
graduate students who desire to devote their lives to a career of 
research in mental health, to young scientists who have already 
received their basic training and require further more advanced 
training, and to mature scientists who desire specialized training 
which will assist them in their work on a specific problem. This 
program provides an essential reservoir of trained personnel for 
work on the many research projects supported by the National Institute 
of Mental Health. Many former research fellows are now receiving 
grants in support of their studies as independent investigators. 
Community Services 

State mental health programs continue to expand and develop at 
an increasing rate. Technical and professional assistance by Institute 
staff and Federal grants-in-aid have proved effective instruments in 
stimulating the development of more adequate State programs. Federal, 
State, and local funds budgeted by the States for community mental 
health services reached a new peak of $6h.Q million in 1959 — a 20 per- 
cent increase ($10.8 million) over the previous year. The Federal 
grants-in-aid of $4 million in 1959 represented only 6 percent of the 
total funds budgeted. About $9 million of the total 1959 funds avail- 
able to the States were budgeted for the expansion of clinical and local 
mental health services. The remainder of the increased funds was used 
to expand State -level staff, research, and training — all areas in which 
there is great need to strengthen present programs. Although there has 
been a rapid growth in the number of clinics since 19^6, when the Mental 



- 18 - 
Health Act was passed, lack of such services, particularly in rural areas 
throughout the United States, still continues to he a major problem. 
State programs received needed help when Federal grants to States were 
increased to $5 million in i960. 

During April 1959, the Institute held the second of a series of 
orientation conferences for State-level personnel. These meetings 
provide an opportunity for State people responsible for mental health 
program planning to share new ideas, and to discuss present programs and 
ways of strengthening and expanding them. Sixty -five representatives 
from selected States attended the meeting. 

In 1955, the Institute evolved the idea of providing support, 
through negotiated contracts, for workshops and conferences held in a 
specific State on a particular problem directly related to the develop- 
ment of the State mental health program. This Technical Assistance 
Projects program has become an effective mechanism for strengthening 
community mental health programs, coordinating mental health activities, 
and bringing to people working on State problems expert knowledge on 
specific subjects. Published reports of these projects are circulated 
to all State mental health programs. 
Alcoholism 

A 5 -year grant in the amount of $1 million has been made to 
the North American Association on Alcoholism Programs (an organiza- 
tion of alcoholism program administrators in the United States and 
Canada) for the purpose of establishing an independent Cooperative 
Commission on the Study of Alcoholism. This Commission will reexamine 



- 19 - 
the whole problem of alcoholism in the United States and Canada and 
recommend future policy and action. Up until now only piecemeal, 
administratively uncoordinated efforts have been made against alcoholism, 
and there has been no single body to review and evaluate what has been 
done and to map a plan of action. For the first time, a unified and 
impartial approach will be made to this urgent and costly problem. 

A special grant was made to the California State Department 
of Public Health to develop instruments for measuring the incidence 
and prevalence of normal alcohol usage patterns, and to provide 
epidemiological information about the nonpathological use of alcoholic 
beverages. A western community of 400 families composed of three 
ethnic groups is the laboratory for a 5-year project aimed at obtain- 
ing information on the entire range of drinking behavior as well as 
other data on the mental health of the community. The project will 
study the prevalence and variety of patterns of maladjustment among 
the three ethnic groups; the extent to which variables in group 
attitudes, values, social structure, and other cultural patterns 
correlate with differences in the mental health of the groups; and 
to what extent any prevalent evidences of maladjustment, including 
drinking behavior, can be understood in terms of personality charac- 
teristics and in terms of cultural forces. 

During 1959 Technical Assistance Projects on alcoholism were 
held in 10 States on such subjects as community resources for the 
rehabilitation of the alcoholic, alcoholism as a mental health problem 
in business and industry, mental health aspects of alcohol education, 



- 20 - 

and the family-centered approach to alcoholism. The conclusions reached 
by these institutes stressed the importance of approaching the subject 
of alcoholism on a community basis and affirmed the efficacy of concerted 
effort in doing something about the problem^ 

The Institute, in^cooperation with the Division of Special 
Health Services, Bureau of State Services, has started planning for a 
series of small working conferences devoted to the general problem of 
automobile accidents associated with drinking of alcohol. Each con- 
ference will be concerned with a particular aspect of the problem; 
e.g., psychological and physiological effects of alochol consumption; 
enforcement, detection, and legal aspects; driving-drinking mortality 
and morbidity statistics; education and mass motivation; and social- 
psychological factors. When this series is completed, the various 
findings will be brought before a major national conference scheduled 
to be held in the spring of 1961. 
Juvenile Delinquency 

The National Institute of Mental Health and the Children's 
Bureau are preparing, at the request of Congress » a report which 
attempts to answer the question: What can and should be done to con- 
trol juvenile delinquency? The report will include both substantive 
and fiscal proposals for action considered to be necessary and 
desirable in attacking the problems of juvenile delinquency in the 
United States. Thorough study of the whole problem will bring 
valuable information, in addition, about child development, particular- 
ly of pathology. The Institute is interested in prevention and treat- 
ment of juvenile delinquency, as well as in research in this field and 



* 21 - 

training of personnel to deal with the problem* Several agencies, 
with support from the Institute, have designed community- wide delin- 
quency control projects to test the effectiveness of present techniques 
and recommended services that appear to hold promise for the prevention 
of delinquency. The Institute is already partially supporting such pro- 
grams in several urban centers. Recently, large-scale support was given 
to initiate a major demonstration project and field experiment for 
delinquency control. 
Mental Health Project Grants 

The Institute's Mental Health Project Grants Program, initiated 
in 195? under authority of Title V of P.L. 911, of the 84th Congress, 
supports projects aimed at new and improved methods for the care, treat- 
ment, and rehabilitation of the mentally ill. During the past 2 
years, emphasis has been placed on studies focused on improved 
hospital care and treatment, improved administration practices, and 
improved community mental health programs. These projects have been 
aimed at the development of new concepts and treatment techniques, 
better integration of service between the hospital and the community, 
a more therapeutic atmosphere within the hospital, better methods of 
early detection and prevention, more effective alternatives to 
hospitalization when indicated,, and improved rehabilitation services 
for discharged patients. Special consideration has been given to 
projects aimed at the above purposes when they pertain to critical 
problem areas such as alcoholism, aging, juvenile delinquency, mental 



- 22 - 
retardation, or schizophrenia. Although most of these projects are 
still in process, some have progressed far enough to permit preliminary 
assessment. In one such project, aimed at establishing and evaluating 
an intensive psychosocial treatment program for chronic psychiatric 
patients, a therapeutic milieu has been created for patients originally 
in a custodial setting. A home-like atmosphere has been introduced; 
there is intensive inservice staff training at all echelons, including 
both professional and nonprofessional personnel; and a broad program 
of patient activities has been introduced. Preliminary indications 
are that such measures are effective in the rehabilitation of hereto- 
fore "chronic" patients. Definite improvement in employee morale is 
also reported. The extension and application of such intensive and 
comprehensive measures hold much promise not only for acutely ill 
patients but also for chronically ill patients, who for so long have 
comprised a major factor in the high costs of public mental hospitals 
and who have been a source of much discouragement. 
Psychopharmacology 

The program of the Institute in psychopharmacology has three 
major components: 

(1) The evaluation of the clinical efficacy of drugs with 
potential utility in the treatment of psychiatric conditions. 

(2) The development and assessment of potentially useful 
methods for the identification and characterization of 
new drugs at the preclinical level. 

(3) The elucidation o f the basic mechanisms of action of 
known psychoactive drugs. 



r^io £•«=">. 



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tn 



- 23 - 

The Institute's Psychopharmacology Service Center, through 
its staff and its special consultants, helps to stimulate research 
by working with individual investigators and with small groups of 
researchers focusing on special problems that need intensive study. 
Psychiatric, pharmacological, psychological, and statistical advisory 
services are made available to investigators. The Center also provides 
on request, bibliographical material and special technical informa- 
tion concerning published and unpublished work in this field. In 
addition, it organizes conferences and works with consultants in the 
analysis of the current state of research in psychopharmacology, using 
these analyses as the basis for its stimulatory activities. 

The effectiveness of these efforts to stimulate research is 
exemplified by the fact that at the September 1959 meeting of the 
American Psychological Association approximately one -third of the 
papers directly relevant to psychopharmacology reported work which is 
being supported by Institute grants. These papers covered a wide 
range of research, much of which has clinical implications. Some 
described new or modified techniques which might be used to screen 
drugs for behavioral or psychological effects. Others reported 
investigations of the effects of specific drugs on the behavior or 
psychological test performance of human or animal subjects. Some 
dealt with studies of the sites or mechanisms of action of specific 
drugs, some with methodological problems. One described experimental 
work on a test of hypothalamic excitability that may prove helpful in 
psychiatric diagnosis. 



- 2^~ 

Conclusion 

To continue the vital work of the Institute and consolidate 

the gains made during the past year, the appropriation request for 

1961 is a total of $67,563,000. This compares with the appropriation 

of $68,090,000 for I960. This allowance for 1961 will provide for the 

continuation of I960 program levels in all activities. An adjustment 

downward of $3,850,000 reflects the nonrecurring adjustment of project 

period starting dates of training grants. An increase of $3,208,000 

will be available for additional support of research grants. 

The request for 1961 is distributed among program activities 

as follows: 

Research projects $26,690,000 

.Research fellowships 1,996,000 

Training grants 22,356,000 

State control programs 5,000,000 

Research 7,697,000 

Review and approval of grants 1,293,000 

Training activities 100,000 

Professional and technical assistance- 1,926,000 

Administration 505,000 

Total - $67,563,000 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Heart Institute 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
fcr 
"National Heart Institute" 



Mr. Chairman and Members of the Committee: 

The year I960 has been one of substantial progress toward 
achievement of the program goals of the National Heart Institute. 
Expanded activities in our laboratories at Bethesda and those sup- 
ported by grants in other institutions have been productive in terms 
of research results. Increased funds provided have also favorably 
influenced the development of needed research manpower and of com- 
munity heart disease programs. Furthermore, emphasis has been given 
to a number of areas of particular interest, such as analysis of fats 
in atherosclerosis research, blood coagulation and clot dissolution, 
epidemiological studies, drug development and evaluation, and primate 
research centers. 

Diseases of the heart and blood vessels took 893,489 lives 
in 1958. Death rates for some types of cardiovascular disease, 
including rheumatic heart disease and hypertension, have decreased 
in the past nine years. The rate for arteriosclerotic heart disease, 
however, the component which includes coronary disease or "heart 
attacks", climbed over 30 percent from 201 per 100,000 population 
in 1949 to 266 in 1958. 



- 2 - 

Important advances continued to be made against the major 
types of heart disease. In atherosclerosis, understanding of the 
hormones, protein structures, enzymes, and physiologic mechanisms 
involved in storage, transport and utilization of fatty substances 
was increased during the year. Attention has also centered on 
dietary and other means of lowering blood cholesterol as possible 
measures for controlling the disease, and the role of stress as a 
factor in elevating blood cholesterol levels has been further 
elucidated. 

In the field of hypertension, the development of drugs for 
reducing high blood pressure has progressed. Knowledge that certain 
enzyme inhibitors can be used for lowering blood pressure has opened 
a new area of research which appears most promising. In cerebro- 
vascular disease, the application of X-ray methods for visualizing 
the blood supply to the brain has shown that flow is often blocked 
in surgically accessible blood vessels in the upper chest and neck. 
A large-scale study is under way for the selection of operable 
patients in the hope that the progress of occlusive disease leading 
to strokes may be averted in such individuals. 

An important development in the control and prevention of 
rheumatic fever was the recent validation of the fluorescent anti- 
body technique in field tests. The technique, which makes possible 
rapid identification of Group A beta hemolytic streptococci, may 



- 3 - 
well lead to ultimate eradication of rheumatic fever and rheumatic 
heart disease. Through heart disease control activities, the 
widest possible application of the new technique is being fostered 
by providing training and furnishing requisite equipment to the 
States. 

The appropriation request for 1961 is a total of $63,162,000 
as compared with the appropriation of $62,237,000 for 1960. This 
allowance for 1961 will provide for the continuation of 1960 program 
levels in all activities and will permit some increase in grants 
for research projects and minor increases in the direct research 
activities of the Heart Institute. This request for 1961 is 
distributed among program activities as follows: 
Grants : 

Research projects $37,115,000 

Research fellowships 2,663,000 

Training 8,588,000 

State control programs 3,125,000 

Direct operations : 

Research 8,359,000 

Review and approval of grants ....... 1,152,000 

Training activities 185,000 

Professional and technical assistance 1,729,000 

Administration 246,000 

Total 63,162,000 



OPENING STATEMENT 

by 

Director, National Heart Institute 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"National Heart Institute" 



Mr. Chairman and Members of the Committee: 

This year has been one of substantial progress toward achievement of 
the program goals of the National Heart Institute, Advances have been 
registered along every front from basic laboratory work to practical 
clinical application. 

The past few years have seen many important developments which, in 
themselves, provide evidence of the fruitfulness of the Institute's approach 
to the cardiovascular diseases. Some of these have, in addition, culminated 
in program efforts which appear to offer much future promise c In the Heart 
Institute's intramural research, for example, the development of a sensitive 
detection device for gas chromatography is enabling much research relating 
to fats and atherosclerosis that was not previously possible. Similarly, 
basic investigations on serotonin and norepinephrine, leading to the 
knowledge that inhibition of the enzyme, monoamine oxidase, can produce 
marked lowering of blood pressure, has opened a new area of research in 
hypertension. The capacity use of patient beds allotted to the Heart Insti- 
tute in the Clinical Center is another instance of research program 
development, permitting a chain of integrated studies throughout the range of 
medical investigation from laboratory exploration to clinical testing in 



- 2 - 
humans. In each of the other major areas of the Institute's total program — 
support of research, training, and application of knowledge—correspondingly 
significant developments have occurred. This statement will present for 
the Committee some of the recent achievements and activities in the 
strengthened effort against heart and blood vessel diseases. 

PRESENT STATUS OF HEART DISEASE 

Diseases of the cardiovascular system took 893,489 lives in 1958. 
Arteriosclerotic heart disease, the component which includes coronary 
disease or "heart attacks", accounted for over half of the total--461,373 
deaths. Cerebrovascular lesions, including strokes and other blood vessel 
disease in the brain, was second in numerical importance with 190,758 deaths. 
Hypertension, with or without accompanying heart disease, accounted for 
87,732. The rank order of mortality for other sizable components of the 
cardiovascular category was: non-rheumatic chronic endocarditis and other 
heart muscle degeneration- -58, 595; general arteriosclerosis--34,443; and 
rheumatic fever and rheumatic heart disease-- 18, 796. 

The death rate for diseases of the cardiovascular system has increased 
somewhat in the last nine years, from 485 per 100,000 population in 1949 to 
516 in 1958. It is revealing in this connection, however, to compare the 
rates for the various components of the cardiovascular category for these 
two years. Death rates for rheumatic fever and rheumatic heart disease, for 
non-rheumatic endocarditis and other myocardial degeneration, and for hyper- 
tension—all showed declines in 1958 from 1949. The rates for general 
arteriosclerosis remained about the same. But the rates for the two largest 



- 3 - 
componeiits--arteriosclerotic heart disease and cerebrovascular lesions- -were 
both higher for 1958 than for 1949 . The death rate for arteriosclerotic 
heart disease climbed over 30 percent from 201 per 100,000 population in 1949 
to 266 in 1958. 

HEART INSTITUTE RESEARCH 

The National Heart Institute is engaged in research directed at 
understanding the life processes in which cardiovascular disease is rooted 
as well as research aimed at controlling these disorders. Biological science 
has the same kind of relationship to clinical medicine and its devices for 
healing that physical science has to engineering and its devices for 
construction and destruction- -the relationship of any science to the 
technology it supports. The technology is dependent upon and inseparable 
from its supporting science. 

Although the Heart Institute exists to gain control of cardiovascular 
disease, and conventional reporting practices dictate communication to the 
non-scientific public in terms of this vitally useful goal, scientific 
research which is concerned only with knowledge is the necessary means to 
that useful goal. There must be an awareness of the means as well as the 
ends for a sound image of the way progress in medical research is made. 

Our hope of understanding the causes of the great cardiovascular 
diseases that are our chief cause of death rests upon gaining insight into 
the basic biochemical and physiological processes among which these disorders 
arise. Our understanding of the causes of cardiovascular disease is limited 
by our limited understanding of these basic phenomena. 



- 4 - 
One of the primary objectives of the intramural research program has 
therefore been to gain a more effective understanding of these phenomena. 
Important progress has been made during 1959 in this purely scientific 
(knowledge- seeking) effort. Pursued freely in cooperation with the practi- 
cal and humanitarian interests of the physician in disease, augmented by a 
normal spirit of competition, curiosity concerning basic phenomena is 
exploited for the conquest of disease. The research environment of the Heart 
Institute is maintained in accordance with this concept. 

Arteriosclerosis 

Because of its high degree of association with abnormalities of blood 
fats, and because it is characterized by the excessive deposition of fatty 
substances in blood vessel walls, arteriosclerosis seems to be due largely 
to abnormal disposition of fats in the body. The progress which has been 
made in intramural research during 1959 has been largely in improved under- 
standing of the hormones, protein structures, enzymes, and physiologic 
mechanisms that are involved in the storage, transport, and utilization of 
fatty substances. 

Earlier studies at this Institute led to the realization that the well- 
known hormone, adrenalin, is involved in the normal mobilization of stored 
fat into the blood to sustain life processes during emergencies. The exten- 
sion of these studies during 1959 has shown that excess adrenalin, acting in 
concert with cortisone, another hormone from the adrenal gland, can cause a 
striking increase in the cholesterol-bearing lipoproteins in the blood. 
Adrenalin is the chemical through which emotional excitement is normally 



- 5 - 
expressed in the tissues (the "chemical analog of emotional stress"), and 
both adrenalin and cortisone secretion increase in subjects exposed to 
physical and emotional stresses. The rise in blood cholesterol that occurs 
in response to these hormones is comparable to the rise in blood cholesterol 
seen in men exposed to various occupational stresses. The discovery of a 
pattern of "stress" hormones that seems to link nervous tension with fat 
transport and utilization suggests a plausible and useful concept of how the 
body may translate high tension living into high blood cholesterol. 

Several methods have been developed for lowering the blood cholesterol 
level by restriction and appropriate supplementation of the diet or by the 
administration of certain drugs which inhibit the synthesis of cholesterol in 
the body. It is important } however, to realize that the exact mechanism by 
which the blood cholesterol is lowered is not understood in any of these 
instances, and it may be that the lowering of the blood cholesterol by such 
abnormal means may be more harmful than beneficial. For instance, in the 
case of two drugs which had been shown to lower blood cholesterol and which 
had advanced to the stage of trial in man, the blood cholesterol was lowered 
but the lowering was associated with accumulation in the blood of abnormal 
substances closely related to cholesterol. One of these drugs has been 
recently and widely introduced for clinical trial as an experimental drug for 
reducing the blood cholesterol. Studies in the Heart Institute have shown that 
although the blood cholesterol is, indeed, lowered, the immediate chemical 
precursor of cholesterol, normally absent from the blood, appears in appreciable 
amounts. Whether this substance is any more or less likely than cholesterol 



- 6 - 
to produce the artery-clogging lesions of atherosclerosis is uncertain, and 
the possible other effects of this abnormal sterol remain to be determined. 
Such findings, however, point up a major question with regard to lowering of 
blood cholesterol--should an attempt be made to lower the level by a direct 
approach or is it essential to learn why the blood cholesterol is high in 
those prone to develop atherosclerosis and direct the attack at the underlying 
cause? The further problems which may be produced by lowering the blood 
cholesterol remain to be determined, but certainly the answers lie in a more 
complete understanding of the many functions of cholesterol in the body-- 
especially its role in the intricate protein vehicles (the lipoproteins) that 
carry the fatty acid energy of food to storage or consumption in the tissues, 
its role in the maintenance of cell structure and its behavior as a precursor 
for vital hormones. 

The relatively recent finding that the transport of saturated fatty 
acids, such as those of animal origin, seems to require the mobilization of 
more cholesterol than the transport of the unsaturated ones of vegetable 
origin has directed attention to the problem of the specific fatty acid 
composition of food and body fats. The differentiation among different fats 
with regard to the identity of their fatty acids has hitherto received 
relatively little attention because of a lack of analytical tools for 
separating and quantifying them as well as a failure to appreciate the 
possible importance of such differentiation. Each fat molecule contains 
three fatty acids, each of which has as its backbone a long chain of carbon 
atoms . The carbon chain may vary in length from 10 to 12 atoms to more than 



- 7 - 
twice that number and may contain "double bonds" (points of unsaturation) 
at as many as three points. There are therefore many combinations and 
permutations and the identity of a fat can be clear only when its fatty 
acid composition is known. The recent introduction of an instrument known 
as the gas chromatograph brought within the realm of feasibility the 
separation and measurement of the exact composition of fats. The method 
has required considerable adaptation which has been achieved through the 
cooperative efforts of a number of groups and to which teams in the Heart 
Institute have made important contributions. Chemists in the Laboratory of 
the Chemistry of Natural Products have made technical advances in the 
procedures and materials used for the fractionation of several types of fats 
of medical interest. The methods for measuring infinitesimal quantities of 
materials derived from the separation process have been improved and 
increased some tenfold in sensitivity by the design , in the NHI Laboratory 
of Technical Development, of a radio frequency discharge detector capable of 
accurately quantifying amounts measured in billionths of an ounce. The 
application of these techniques will make it possible to study the members of 
the heterogeneous class of fats as individual substances, which may well 
behave in quite individual fashion. 

Hypertension 

In the Heart Institute, as elsewhere, the research on hypertension 
has two aims. One is to clarify the mechanisms by which blood pressure is 
regulated and the nature of the disturbances of this regulation in hyper- 
tension. The other is the direct development of drugs and other devices for 



- 8 - 
lowering high blood pressure and reducing its threat to the individual who 
has developed symptoms of hypertension. 

Although in recent years there have been considerable improvements in 
the drug treatment of hypertension with an appreciable brightening of the 
outlook for the average patient with the disease, the fundamental causes 
of this widespread disease are largely unknown. Because hypertension of 
any degree increases the risk of arteriosclerosis and coronary artery 
disease, there is, beyond the continued improvement in the effectiveness 
of drugs, a real need for preventive as well as ameliorative measures. 
Treatment with any drug requires that the physician balance against the 
anticipated benefits the possibility of undesirable effects. In the 
management of hypertension the fact that most of the available drugs fall 
far short of ideal means that many patients are considered not sufficiently 
ill to require drug therapy. As the drugs are improved not only will the 
more severely hypertensive individuals be more effectively treated, but more 
of those patients v.ith lesser elevations of blood pressure can be expected 
to come under control before there is further advance in the disturbance. 

Although there is always the possibility of turning up a useful drug 
through the random testing of chemical compounds for their effects on the 
condition or variable to be treated, such procedures have an extremely low 
efficiency. Much more is to be expected s when the field can be narrowed, 
through an understanding of specific mechanisms, to compounds of a specific 
chemical type and aimed at affecting a specific biochemical mechanism for 
which the requirements can be determined. In this regard, the discovery 



- 9 - 
of one series after another of drugs which lower blood pressure has been 
largely dependent upon our understanding of the nervous, hormonal and 
muscular components in the maintenance of blood pressure. It is illustrative 
of the importance of this more rational approach that two promising groups 
of compounds, recently developed in considerable measure through the efforts 
of Heart Institute investigators, have, under the usual conditions for 
screening, no blood pressure lowering activity in animal tests. Yet both 
have important effects in patients with hypertension. 

Most of the currently used anti-hypertensive drugs exert their 
effects on regulatory systems which had been recognized and at least 
partially elucidated before the possibility of manipulating them for the 
management of hypertension had even been considered. The control of the 
caliber of blood vessels by the activities of the autonomic nervous system 
has been known for many years and the surgical interruption of these nervous 
pathways by the procedure known as sympathectomy was one of the earliest 
procedures aimed at the treatment of hypertension. It then became possible 
to accomplish the same effect with drugs which paralyze the autonomic 
nervous system. The chemical structure necessary for such activity is now 
well known and a number of such substances are in general use. The many 
undesirable effects of paralyzing the sympathetic nervous pathways has 
prompted a continued search for drugs with more specific effects. Since 
the autonomic nervous system includes two subdivisions, the sympathetic and 
parasympathetic, and since only the sympathetic is involved in maintaining 
the blood pressure, it was highly significant that the impulses in the 



- 10 - 
sympathetic system are transferred to their target organs by the release of 
the hormone noradrenalin. Thus, by impairing the synthesis or destruction of 
this hormone, it might be possible to modify the transmission of sympathetic 
nervous activity. Again falling back on basic information acquired earlier, 
in considerable part through the efforts of Heart Institute biochemists, it 
was possible to consider the various chemical steps at which the synthesis 
or destruction of noradrenalin might be inhibited. Trial of such compounds 
has shown that they, indeed, do lower the blood pressure in hypertension. 
One group is that of the monoamine oxidase inhibitors, which interfere with 
the enzyme responsible for destroying noradrenalin and other chemically- 
related substances at nerve endings and which have gained wide use in 
psychiatry as "psychic energizers." Trial of one of these compounds in 
hypertension revealed a very high degree of activity and freedom from the 
usual side effects of autonomic nervous system blockers. Unfortunately the 
appearance of another serious side effect-~impairment of vision-=has elimi- 
nated this particular compound from further use. But the knowledge that 
such inhibitors can be used for lowering blood pressure makes possible the 
synthesis of a variety of compounds with similar inhibitory activity which may 
not have this side effect. 

Meanwhile studies are continuing in the quest of other drugs which 
modify the production in the body of amines, the family of highly active 
substances of which adrenalin is a member. 

Congestive Heart Failure 

Congestive heart failure is the group of disturbances which result 



- 11 - 

when the heart is no longer able to meet the demands placed upon it for 
maintaining an adequate circulation to the tissues. It is the end result 
common to all of those cardiovascular diseases which place an increased load 
upon the heart. For many years, the fundamental steps in the response of the 
heart to load have been formulated in accord with Starling's Law of the 
Heart. This law describes the behavior of the heart as its filling 
pressure is modified--stating that, as filling pressure is increased, the 
heart muscle fibers lengthen, and as the fibers lengthen, the heart's out- 
put with each beat increases. However, as the lengthening of the fibers 
increases a point of diminishing returns is reached beyond which further 
lengthening leads to decreases rather than increases in output . This turning 
point where the relationship between filling pressure and output becomes 
inverted represents the onset of heart failure. 

Findings in the Laboratory of Cardiovascular Physiology during 1959 
modify and greatly extend Starling's classic Law of the Heart. These 
physiological studies were aimed at learning how the performance of the 
heart as a pump is changed to meet the demands of the tissues for blood and 
how these demands are communicated to the heart. 

These studies have provided a unified concept of the basic control of 
cardiac output by the autonomic nervous system overlying and integrated 
with the intrinsic responses of the heart muscle described by Starling's Law. 
The experiments have shown that impulses from the sympathetic ("adrenalin- 
transmitting") part of the autonomic system can greatly increase heart work 
even when filling pressure and fiber length remain unchanged. Changes in 



- 12 - 
pressure in certain of the major blood vessels of the circulation are 
monitored by nervous receptors, and signals are transmitted to the heart via 
the sympathetic nerves. In response to such signals the contractile, pumping 
force of the heart muscle and along with it the heart's output of blood are 
increased or decreased so as to keep pressure and flow to vital organs at the 
desired level. The relationship between filling pressure and output 
described by Starling's Law is thus adjusted upward or downward through 
automatic nervous controls in accord with the needs of the body. Thus, in 
considering the factors that contribute to the regulation of heart output 
(and that might usefully be controlled in heart disease and failure) 
therapeutics will have another important component—sympathetic nervous 
activity and its equivalent, adrenalin release--to manipulate. 

Another important line of scientific discovery has to do with the 
mechanisms by which the balance of sodium and potassium ions is maintained 
across cell membranes. This balance governs the fluid volume not only of 
the individual cell, but, through its operation in the kidney, controls the 
volume of the blood and the spaces between cells. The contraction of 
muscle, the conduction of nerve impulse--in fact the life of every cell-- 
depends on the performance of poorly understood mechanisms by which sodium 
and potassium ions are transported across cell membranes. Only in the last 
few years has it been recognized that the action of digitalis in modifying 
heart action, used empirically in treatment for several hundred years, is 
due to its effect on these ion-transporting mechanisms. 

Some of these ion transport mechanisms, particularly in the kidney, 
are controlled by hormones. Aldosterone, a steroid from the cortex of the 



- 13 - 
adrenal glands, causes the kidneys to withhold sodium, and consequently 
water, from the urine. Without this salt-retaining hormonal activity, 
excessive urinary loss of salt and water, and eventually death, result. But 
in persons with the edema of heart, kidney and liver disease, an excess of 
aldosterone is secreted. Institute research therefore includes a major 
effort directed at studying the mechanisms that regulate, aldosterone 
secretion from the adrenal cortex. 

During 1959, evidence was obtained by NIH physiologists that still 
another hormone appears in the blood to stimulate aldosterone secretion 
during congestive heart failure. Further steps are being taken to determine 
the nature and source of this new hormone. At present it seems most probably 
to originate in a brain structure--possibly closely related to the pituitary 
gland. Each link, exposed by scientific inquiry, in the chain of events 
leading to abnormal sodium retention exposes another point for clinical 
attack on the problem of cardiac edema. 

RESEARCH GRANTS 

Methods of treatment and means of prevention of cardiovascular 
diseases have been improved during the past year through research supported 
by grants, from the National Heart Institute. Some of these accomplishments, 
and the avenues of investigation being used, are described below. 

Arteriosclerosis 

Research workers in the field of arteriosclerosis, and coronary heart 
disease in particular, are pursuing the answers to such cogent questions 



- 14 - 
as: What dietary recommendations can the medical profession make to patients 
who have coronary disease? Can a practical food pattern be developed for the 
whole population that will be effective in reducing serum cholesterol levels 
and maintaining them at lowered levels to decrease the risk of coronary heart 
disease? What is the effect of "stress" on the development of the disease? 

It is generally agreed that blood lipids are deeply implicated in 
atherosclerosis. Studies are being made of the hows and whys of their action 
on arteries. A feeding experiment in man indicates that two highly unsaturated 
dietary fats--one poor in essential fatty acids and sterols and the other rich 
in these two factors--have similar effects on human serum lipid levels, 
implying that the unsaturation of dietary fat rather than its content of 
essential fatty acids and sterols is important in lowering serum lipids. 
Another study of patients maintained on a fat-free diet long enough to 
reduce plasma lipid levels to a plateau shows that the further lowering of 
plasma lipids is due to the addition of unsaturated fat to the diet rather 
than to the subtraction of other materials. 

Big strides are being made in development of technical devices and 
procedures for the separation and analysis of biologically important fatty 
acids. For example, in gas chromatography, by which fats may be analyzed 
with unprecedented sensitivity, capillary columns are found to possess an 
efficiency exceeding that of conventional columns by several hundred percent. 
Availability of such methods should bring forth new information on the role 
of these fatty acids in health and disease. 

The stress imposed upon man in his quest for economic or social 
"success" may be playing havoc with his health. A study of a group of 



- 15 - 
patients with clinical evidence of coronary artery disease suggests that 
circumstances interpreted by the patients as stressful elevated the serum 
cholesterol level, when diet and exercise were held constant. 

A variety of drugs has evolved for use in arteriosclerotic disease, 
but their value in man is not yet established. Soy phosphatides produce 
promising results in atheromatous rabbits. A pituitary hormone appears to 
stimulate mobilization of fat from adipose tissue. The quest for drugs which 
will lower serum cholesterol is engaging the attention of many investigators. 
Use of nicotinic acid for this purpose has produced conflicting results, and 
additional controlled studies are indicated. This substance is also reported 
to promote fibrinolytic activity and is being studied for use in the therapy 
of thrombo- embolic diseases. Consistent lowering of serum cholesterol levels 
following oral administration of neomycin--an antibiotic--is reported. 

Hypertension 

Although elevation of arterial blood pressure is the basic attribute 
of all forms of hypertension, the etiology of the various clinical types 
remains uncertain. "Essential" hypertension and the hypertension that results 
from certain kidney diseases, for example, may be unrelated so far as causation 
is concerned. On the other hand, it is possible that such secondary 
hypertension tends to occur chiefly in persons who are highly susceptible 
to the "essential" type of hypertension. Studies are underway to clarify 
these points. One in particular is aimed at ascertaining the occurrence of 
hypertension among relatives of known hypertensives, to study the 



- 16 - 
physiological s socio-economic, and environmental characteristics of 
individuals in whom hypertension has or has not developed, and ultimately to 
determine the effect of familial factors which will throw some light on the 
comparative roles of inherited and acquired factors in the pathogenesis of 
hypertension. 

Disability and death due to hypertension are often more closely linked 
to atherosclerosis than to an elevation of arterial pressure per se. The 
experimental production of hypertension, the effects of dietary abnormalities, 
kidney removal, and the use of kidney transplants in animals are methods 
being used to study the relationship between increases of blood pressure and 
the tendency to arteriosclerosis. 

A host of drugs for the alleviation of high blood pressure are being 
evaluated for clinical use. Their mechanisms and sites of action are being 
determined in animals by intricate techniques whereby central and peripheral 
activity can be distinguished, prior to therapeutic use in patients. 

Rheumatic Fever and Rheumatic Heart Disease 

Investigations into the chain of events leading to rheumatic fever 
have solidified the concept that it usually follows Group A streptococcal 
infections. But the mechanisms by which the disease is initiated, the 
immunologic processes involved, the roles of environmental factors and of 
genetic tendency still beg for clarification. Preliminary data from a study 
of streptococcal infection among school children indicate that live 
streptococcal bacteria can be cultured from throat swabs of a large 
percentage of children during the school year. But the rate of clinically 



- 17 - 
manifest streptococcal infection has remained relatively low. The 
significance of the positive cultures is being intensively studied by 
addition of serologic techniques to aid in the diagnosis of streptococcal 
illness and to detect the presence of coincident viral respiratory 
illnesses, for any viral-bacterial relationships that might bear on the 
virulence of streptococcal infection. Various types of drugs are being 
evaluated in the prevention and treatment of rheumatic fever „ The use of 
intramuscular injections of penicillin in a three-year study of prophylactic 
methods proved more effective than either oral penicillin or sulfadiazine. 
The current studies will be expanded to verify dose relationships. 

A direct approach to the correction of heart damage due to rheumatic 
heart disease is the replacement of diseased aortic and mitral valves by 
better and safer prosthetic ones with moving leaflets. But the problems of 
adequate position and anchorage of artificial valves remain troublesome. 

Surgery 

In addition to the advances in surgery cited elsewhere, there is an 
active search for better methods of arresting and reviving the heart in 
conjunction with open heart surgery, such as the use of various combinations 
of drugs, perfusion of the heart with oxygenated and decalcified blood, or 
perfusion with cooled blood. Recent findings indicate that the inclusion 
of devices for cooling body tissues (hypothermia) extends the time the 
surgeon has to work within the heart beyond the periods allowed by cardiac 
arrest or extracorporeal circulation alone. The requirement for large 
volumes of blood during open heart surgery may be reduced as a result of 



- 18 - 
the experimental finding that perfusion of only a few vital organs rather 
than the entire body is sufficient to permit complete recovery after 
circulatory arrest even for periods longer than an hour. Particularly 
encouraging in the field of tissue and organ transplantation is the 
apparently successful transplantation of a kidney between fraternal (not 
identical) twins. This constitutes a major advance in terms of the 
forbidding problem of the "host rejection" response to genetically different 
tissues. 

Cerebrovascular Disease 

The application of X-ray methods for visualizing the blood supply 
to the brain in cerebrovascular disease has shown a high frequency of blocked 
flow in such surgically accessible vessels as the arteries in the upper 
chest and neck. A large scale study is under way for the selection of 
operable patients in the hope of averting in such individuals the progress 
of occlusive disease that may lead to strokes. Investigators are also seeking 
a means to prevent the thrombosis of small blood vessels in the skull 
following surgery, without the use of hazardous anticoagulants. If this is 
successful, it may have application to other small blood vessels of the body 
as well, such as the coronary arteries. Nutritional factors are being studied 
for their effect on cerebral function as they are for their effect on 
arteriosc lerosis . 



- 19 - 
DEVELOPMENTS IN SPECIAL AREAS 
Epidemiology 

Because of the multitude of factors which may be related to the 
development and course of cardiovascular disease, an approach which studies 
the various factors as they naturally occur in population groups offers 
unique promise. Several factors in our mode of life are suspect, including 
mental stress, physical activity, smoking habits, and diet. These are not 
easily measured, and associations with disease do not necessarily indicate 
cause and effect relationships. 

Studies are being done among unique racial groups, with similar 
ethnic origin, cultural background, dietary habits and geographic location, 
to determine any possible correlation with the incidence of cardiovascular 
disease. One seven-year study on 1800 men to determine the incidence of 
coronary heart disease in relation to various biological and social factors 
indicates that among white males significant differences occur according to 
relative weight, blood pressure levels, serum cholesterol levels and family 
history of heart disease. No differences in incidence were observed according 
to physical activity of the job class (professional, clerical, unskilled 
laborer), or to economic status. Another study in progress, on the 
epidemiology of congenital heart disease, is pursuing various lines; the 
relationship to meteoro logic conditions, radiologic fall-out, pregnancy 
histories, blood types of children and mothers, virus content of serum and 
heart tissue, race, ethnic origin, income, education and housing. 



- 20 - 

Blood Coagulation aid Thrombolysis 

The clinical problems presented by blood coagulation disturbances 
are frequent, challenging and extensive, including the life-long difficulties 
of the hemophiliac (bleeder);, gangrenous states in the limbs of the body due 
to obstruction of blood vessels, severe paralytic strokes caused by cerebro- 
vascular occlusion and sudden death due to coronary thrombosis or pulmonary 
embolism. In studies on bleeding disorders due to the decreased amount of 
a clotting factor in the blood 9 attempts are being made to isolate the 
necessary factor from sources of normal blood plasma and to test its ability 
to remedy the defect. The coagulation disturbances associated with arterio- 
sclerosis are the subject of considerable research activity in order to 
elucidate the factors that increase blood coagulability and impair clot 
dissolution and also to develop means of preventing or counteracting these 
disturbances. A system recently devised for observing coagulation in 
flowing human blood should make further important studies possible. In the 
area of anticoagulant drugs, the definitive characterization of an anti- 
thrombin isolated from blood now seems possible. Several substances under 
study are reported to have potential for counteracting the danger which 
might result from excessive anticoagulant levels in the blood. 

In addition to these studies concerning the prevention of clotting, 
research is actively continuing on the factors involved in thrombolysis, the 
dissolution of clots. For example, investigators are attempting to isolate 
thrombolytic agents from natural sources such as soil fungi. Plasmin, an 
enzyme normally occurring in blood, has been used to dissolve blood clots 



- 21 - 
experimentally produced in the coronary arteries of test animals. New 
knowledge is also being gained about a number of substances, such as strep- 
tokinase, that promote clot lysis by increasing the production of active 
plasmin in the body. The development of a practical method for the use of 
streptokinase on patients with occlusive blood vessel clots is under 
investigation. 

Drug Research 

In the search for improved methods for the treatment of cardiovascular 
diseases, research effort will focus on the evaluation of new drugs as well 
as the testing of known pharmaceuticals under new experimental and clinical 
conditions. In addition to the studies on drugs discussed in relation to 
arteriosclerosis, other workers in this field are investigating the use of 
hormones such as a synthetic compound related to estrogen that decreases 
serum cholesterol and has little or no feminizing power in males, the 
value of purified blood components in regulating the formation and lysis of 
clots that can occlude blood vessels, and in connection with arterial 
surgery, the identification of various chemicals that can adhere to the 
inner surface of the arterial wall and minimize clot formation. 

Clinical trials of a new drug, guanethidine, indicate its ability to 
reduce blood pressure in renal and essential hypertension without the side 
effects accompanying other commonly used agents. Other advances in cardio- 
vascular drug research that show promise include a compound that may be 
clinically useful in treating disturbances in the rhythmical contractions 



- 22 - 
of the heart and the isolation and testing of plant substances of potential 
value for patients with heart failure. 

Progress is being made by the Heart Institute in developing a broad 
program of drug development. Contacts with the pharmaceutical industry as 
a whole were initiated through the Pharmaceutical Manufacturers Association, 
a national organization whose medical section has established a Sub-committee 
on Cardiovascular Agents. Partly through the work of the Sub-committee and 
partly through the initiative of individual firms, direct relationships 
have been developed between the Heart Institute and at least 20 pharmaceutical 
houses. A National Heart Institute sponsored meeting on standards and 
standardization of methods needed for the orderly development of new cardio- 
vascular drugs was held in January of this year. More than a dozen 
pharmaceutical firms were represented at this conference. 

Primate Centers 

The need for national facilities for cardiovascular research on sub- 
human primates has been of major concern. Provision by the Congress of funds 
for this purpose has enabled steps to be taken toward the establishment of 
two centers. Thirteen possible sites in various parts of the country were 
visited by a Special committee of the National Advisory Heart Council and a 
number of these were judged to have sufficient local interest and center 
possibilities. Several applications have since been received, which are 
being reviewed by the National Advisory Committee on Primates in the Division 
of Research Grants prior to final review by the National Advisory Heart 
Council in March 1960. 



- 23 - 
International Activities 

A small number of research grants have been made to investigators to 
other countries o Also s this year the Heart Institute awarded its first 
training grant to a foreign scientist- -A Danish world authority on ion 
transport across cell membranes. This training program has attracted many 
young researchers from other countries as well as the United States. 

The support of conferences , both national and international, on 
matters of significance to cardiovascular disease has continued and 
broadened. An international meeting in Switzerland attended by 85 
specialists on blood coagulation dealt with new clotting factors--a matter 
of increasing importance to patients threatened with the formation of 
clots in their blood vessels and to physicians who wish to treat these people 
effectively with anticoagulants. In connection with this conference 9 
scientists from 16 countries agreed on one new item to be added to their 
existing list of eight "accepted" clotting factors and agreed on symbolic 
names for all nine. This represents progress, as these agreements tend 
to increase effective communication among scientists independent of language 
differences, and will speed up the application of new knowledge by physicians 
Grant-supported conferences in this country have dealt with blood platelets 
(another aspect of clotting), control exercised on the cardiovascular system 
by the central nervous system, and the epidemiology of the cardiorespiratory 
diseases. Arrangements were made for leading foreign scientists to parti- 
cipate in all of these. 



- 24 - 
TRAINING 

The National Heart Institute now supports over 250 training programs, 
with nearly all medical schools participating. They range from intensive 
programs in such fields as lipid chemistry technology and cardiac surgical 
research to broad inter-disciplinary training in clinical investigation. 
Noteworthy, as a result of the increased Congressional appropriation this 
year, has been the development of mu It i- departmental programs where several 
laboratories with related research goals pool their training resources to 
offer broadly diversified, carefully structured research training oppor- 
tunity. We expect that more programs of this type will be developed in 
the coming year, especially programs which join preclinical departments 
(or even components of other colleges such as electrical engineering 
departments or biology departments) with clinical departments in order more 
rapidly and authoritatively to bring the research technologies of basic 
sciences into clinical cardiovascular research. 

Two other programs where much needed further expansion has become 
possible as a result of the increased funds for training this year are 

(1) training investigators in the exacting methods of drug evaluation and 

(2) development of training in areas such as medical electronics, compara- 
tive cardiology, medical genetics, and others where special needs are 
apparent . 

Further, as a pilot program it is planned to select certain 
academically oriented and otherwise qualified hospitals in large communitie s 
where there are no medical schools, and develop training activities which 



- 25 - 
will encourage the growth of both basic and applied clinical research in the 
hospitals. This program has three aims; (1) to increase the number of loci 
of research in the country, (2) to improve the scientific and academic 
atmosphere of these institutions so that they may become nuclei from which 
medical schools or other graduate medical educational institutions may in 
time develop, and (3) to bring medical research closer to the practicing 
physician,, 

HEART DISEASE CONTROL 

The heart disease control program provides technical assistance to 
the States in the application of existing and newly developed knowledge of 
the cardiovascular diseases. The increase in funds appropriated for the 
current year has made it possible to increase the number of medical officers 
and others assigned to State, county and local health departments and 
selected clinical groups, An additional 29 medical and nurse officers have 
been assigned, bringing the total to 48, In some instances, the increase 
makes possible the formation of professional teams to strike at vital 
heart disease control problems facing the communities to which officers 
are assigned; in others, it means the addition of facilities to test n*w 
findings and to put to use proved techniques from the laboratories . Some 
officers have assisted in establishing entirely new community programs 
while others have helped the expansion of existing programs by the inclusion 
of important new projects, 

A most dramatic development in the control and prevention of rheumatic 
fever was the validation of the fluorescent antibody technique in field 



- 26 - 
tests carried out in cooperation with the Communicable Disease Center and 
several State health departments. This technique, which makes possible rapid 
identification of Group A beta hemolytic streptococci, may well lead to the 
ultimate eradication of rheumatic fever and rheumatic heart disease* The 
heart disease control program is now seeking to foster the widest possible 
application of this new technique by providing training for State laboratory 
technicians and furnishing States with the requisite equipment. Nearly 
thirty states will have the equipment and trained personnel by February 1960, 
The program is also seeking means for (1) making training in the technique 
available to non- governmental laboratory personnel (2) insuring an adequate 
supply of the critical reagent, (3) providing professional and lay informa- 
tion on the technique, and (4) implementing prevention programs at the local 
level. 

The control program has contributed to the total national effort in 
developmental and applied research in several ways. There are indications 
that new, striking diagnostic aids can be developed which will significantly 
reduce the demands on the physician's time as well as make life-saving 
measures more readily available to the patient. An instrumentation group has 
been formed in the program to provide national leadership in this area. A 
study of the relationship of emotional stress to serum cholesterol levels 
has been completed, showing that a significant increase in mean value for 
serum cholesterol accompanies emotional stress. A survey of obesity patterns 
over a 20=year period showed that overweight children tend to become over- 
weight adults, and that it is difficult to change adult eating patterns. The 



- 27 - 
study suggests that measures to curb obesity should be undertaken in 
childhood if obesity control is to be successful. 

Now in its fifth year is a study of rheumatic fever and rheumatic 
heart disease among college freshmen which is being conducted in cooperation 
with the American College Health Association. In the field of congenital 
heart disease, a study of the heart sounds of 40,000 school children was 
begun last year. Thus far, about 14,000 individual recordings have been made 
and are being studied by pediatricians and cardiologists for possible heart 
defects. The significance of "functional murmurs" found in children 20 years 
ago has been evaluated by recent re- examination. Preliminary results 
largely support the current medical opinion that such murmurs are not 
pathologically significant. 

SUMMARY 

The past year has been one of the most productive since the National 
Heart Institute was established. The expanded activities in our own 
laboratories and those supported by grants in other institutions have been 
rewarding in terms of research results. The increased funds appropriated 
by the Congress have also favorably influenced the development of needed 
research manpower and of community heart disease programs. Because of this 
progress, the outlook for those with cardiovascular disease continues to 
improve . 

In conclusion, Mr. Chairman, the appropriation request for 1961 is 
a total of $63,162,000 as compared with the appropriation of $62,237,000 
for 1960. This allowance for 1961 will provide for the continuation of 



- 28 - 
1960 program levels in all activities and will permit some increase in 
grants for research projects and minor increases in the direct research 
activities of this institute. This request for 1961 is distributed among 
program activities as follows: 
Grants ; 

Research projects $37, 115,000 

Research fellowships 2,663,000 

Training 8,588,000 

State control programs 3,125,000 

Direct operation s; 

Research .,,..,,,..*,,.,«,.».... 8, 359,000 

Review and approval of grants ,»*.....,.» 1,152,000 

Training activities ...............*,.,., 185,000 

Professional and technical assistance , ... 1,729,000 

Administration 246,000 

Total 63,162,000 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Institute of Dental Research 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
Dental Health Activities 



Mr. Chairman and Members of the Committee: 

The following statements will review for this Committee progress 
made by the National Institute of Dental Research, the Division of 
Dental Public Health and the Division of Dental Resources in their 
respective missions to achieve and apply workable methods for the 
detection, prevention and treatment of oral diseases. 

Many aspects of the commonly occurring disorders of the mouth 
and adjacent structures continue to challenge an increasing variety 
of dental investigators today. Moreover, the dental profession is 
cognizant of the increasing responsibility it shares with the other 
health professions for the treatment and prevention of certain systemic 
disorders including among others congenital oral anomalies and oral 
manifestations of diseases such as blood dyscrasia, nutritional 
deficiencies, etc. 

Nineteen sixty has been a year punctuated with achievements of 
important long-term and short-term goals. For example, basic and 
clinical research efforts have expanded not only in our Bethesda 
laboratories but expecially in nonfederal institutions receiving grant 
support throughout the country. Further, the application of what is 



- 2 - 

now known about treatment and control of oral disease has been extended 

and greater emphasis is being placed on advancing public and profes- 
sional awareness of such research findings. 

Undoubtedly, the most significant development for the control of 
tooth decay in the history of preventive dentistry was the discovery 
of the benefits related to fluoridation. However, even in the face of 
this significant advance efforts continue toward the development of 
additional preventive measures. For example, recent experimental data 
from our laboratories provide evidence that a marked reduction in dental 
caries may be effected by dietary supplements of phosphate minerals. 
Clinical studies now under way are designed to extend our knowledge 
of the effects of these compounds on caries reduction. 

In addition, studies with germfree animals have provided 
important new information on the bacterial causes of dental caries, 
as well as on the relationship of the oral flora and various nutri- 
tional factors to tartar formation and the onset and progression of 
periodontal disease. These and related clinical studies have already 
demonstrated that both tartar-like material and periodontal disease can 
occur in the absence of oral bacteria. Data from these experiments 
with the germfree and the gnotobiotic animals, continue to provide a 
firm foundation for totally new concepts in dental research. 

In the area of experimental caries research observations have 
been made this year which indicate that dental caries is an infectious 
and transmissible disease in hamsters and rats. From these findings it 
is evident that the usual source of the caries producing microbial 
flora in young animals is from the alimentary tract of the mother; and 



- 3 - 
that animals lacking this flora may acquire it by cross -infection 
contact with caries-active animals D Work now in progress suggests that 
there may be limitations either in the extent to which the flora of 
one species can be transmitted to another, or in the degree to which it 
will be pathogenic if transmitted. This observation may explain in 
part why previous attempts to induce caries in laboratory animals by 
inoculation of human strains of bacteria have failed,, 

The Dental Health Activities of the Public Health Service embrace 
not only the conduct and support of research and training, but also 
the provision of consultative technical assistance to state and local 
dental programs, and the development of dental resources „ From this 
last area, that of dental resources, we learn, for example, that the 
number of practicing dentists has been losing ground to population 
growth in this country for more than a quarter of a century. If current 
trends continue, the present ratio of 46 per 100,000 population will 
decline to 43 per 100,000 by 1975. 

We must of course, depend on our dental schools to provide us 
not only with more practitioners but with persons trained in teaching 
and research methods. A conservative estimate is that 650 teachers/ 
researchers per year will be needed in the next decade. During 1960, 
progress was seen both in the awarding of additional fellowships, 
primarily in the basic sciences, and in the establishment of seven new 
research training centers and supplemental support to expand current 
training programs. By the end of 1960, after only 3 years of program 
operation, 25 graduate training centers will be supporting approximately 



- 4 - 
130 trainees in both the basic and clinical sciences,, Results from 
this modest but successful program are seen today in the some 40 to 
50 trainees who will complete their training in I960, 

In the area of Research Project Grants, increased funds in 
1960 have provided for active program expansion in the broad areas 
of periodontal disease, oral congenital anomalies (cleft lip/palate) 
and dental caries. At the same time, emphasis was directed toward other 
important facets of dental research, such as oral-systemic interrelation- 
ships of chronic disease, electromyographic studies of the jaw, dental 
radiation investigations, aging studies, and on dental public health 
research. 

Highlight activities of the Division of Dental Resources in 1960 
included assistance to states and regions in planning for needed dental 
school facilities. In addition, an experimental program was launched 
to determine the optimum course requirements for the training of the 
dental chair-side assistant. This study is a logical extension of 
current programs designed to train dental students in the use of such 
assistants. Also under study in I960 were a number of pre- arid poetdental 
payment plans serving specific population groups. 

In the Division of Dental Public Health, emphasis is currently 
being placed on consultative and technical assistance to communities 
of 2,500 population or less, as only 67o of these are now benefiting from 
controlled water fluoridation. Increased funds in 1960 made it possible 
to proceed with implementation of a study to develop a practical system 
for fluoridation of individual home water supplies to meet the needs of 
the approximately 1/3 of our population which does not have access to 
communal water supplies. 



- 5 - 
In conclusion, Mr. Chairman, the appropriation request for 
the Dental Health Activities in 1961 is a total of $11,204,000 as 
compared with the appropriation of $10,019,000 for 1960. This 
allowance for 1961 will provide for the continuation of 1960 program 
levels in all activities and will permit some increase in grants for 
research projects and minor increases in the direct research activities 
which include $400,000 for equipment for the new dental building and 
$34,000 for clinical investigations. This request for 1961 is 
distributed among program activities as follows: 
G rants : 

Research projects --------------$ 5,246,000 

Research fellowships ------------ 650 9 000 

Training 1,009,000 

Direct Operations : 

Research ----- 2,021,000 

Review and approval of grants -------- 217,000 

Professional and technical assistance - - - - 1,192,000 

Coordination & development of dental resources 774,000 
Administration --------------- 95,000 

TOTAL 11,204,000 



OPENING STATEMENT 
by 
Director, National Institute of Dental Research 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"Dental Health Activities" 



Mr. Chairman and Members of the Committee: 

The following statements will review for this Committee, 
progress made by the National Institute of Dental Research, the 
Division of Dental Public Health and the Division of Dental Resources 
in their respective missions to achieve and apply workable methods for 
the detection, prevention and treatment of oral diseases. 

Many aspects of the commonly occurring disorders of the mouth 
and adjacent structures continue to challenge an increasing variety 
of dental investigators today. Nevertheless, we consider this past 
year to have been a very fruitful one--a year that has witnessed 
achievements of certain long-term and short-term goals. Basic and 
clinical research efforts have expanded not only in our Bethesda 
laboratories but especially in nonfederal institutions receiving 
grant support throughout the country. Further, the application of 
what is now known about treatment and control of oral diseases has 
been extended in a number of areas and greater emphasis is being 
placed on advancing public awareness of these research findings. 
Additional programs designed to increase the number and quality of 
trained scientific investigators, teachers, and skilled clinicians 
oriented in the dental sciences were also initiated during the past 
year. 



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Some of the accomplishments and developments of the Dental 
Health Activities' total program which have occurred during the 
current year are set forth in the ensuing pages of this statement. 
The budget proposal before you requests an appropriation of 
$11,204,000 for support of these activities in 1961. 
Oral Disease Today 

Nine out of every ten persons in these United States are 
affected by one or more forms of dental disease — tooth decay, perio- 
dontal disease, fluorosis, malocclusion, cleft lip and palate and 
oral cancer. In spite of the 1.7 billion dollars expended each year 
for dental services, the nation's accumulated dental needs are several 
times greater than the needs currently being met. Tooth decay continues 
to dominate the field of dental disease; however, statistics now being 
gathered show that periodontal disease is currently a problem of 
major national importance and might soon pass caries as the leading 
cause of tooth loss in this country. Available clinical data tell 
us, for example, that 22.5 million persons now require treatment or 
extractions for periodontal disease and an additional 40 million 
persons need preventive treatment. To meet these treatment needs 
alone would involve close to three-quarters of a billion dollars in 
dental bills. 

Of further concern today is the knowledge that more than 4 
per cent of all cancer occurs in the oral cavity, and it is five times 
more prevalent in the oral cavity of males than females. Cancer of 
the head and neck is responsible annually for the death of approxi- 
mately 20,000 persons in this country. 



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Consideration of these overall statistics associated with 
oral disease serve to demonstrate the difficult problems that still 
await the attention of dental scientists. However, new findings 
introduced through laboratory and clinical research during the past 
year have added significantly to the existing body of knowledge in 
terms of diagnosis, treatment, and general understanding of disease 
mechanisms. 

The Dental Health Activities of the Public Health Service 
function today in the conduct and support of research and training, 
the provision of consultative technical assistance to state and 
local dental programs, and the development of dental resources. In 
this last area, that of dental resources, we know that the number of 
practicing dentists has been losing ground to population growth in this 
country for more than a quarter of a century. During this period, the 
number of dental practitioners actually serving the civilian population 
has fallen from 58 to 46 per 100,000 persons. If current trends 
continue, this ratio will decline to 43 per 100,000 persons by 1975. 

We must, of course, depend on our dental schools to provide 
us not only with more practitioners but with persons trained in 
teaching and research methods. At the present time, dental schools 
almost uniformly report pressing problems in faculty recruitment and 
retention. To a disturbing degree faculty positions are being filled 
by practitioners who devote only a few hours a week to part-time 
teaching. Further, we know that strengthening the dental faculties by 
increasing the permanent full-time positions, with adequate opportun- 
ities for research and experimentation must receive priority support 



- 4 - 

beyond our present level. It is against this background of 
recognized dental health needs that we wish to report to the 
Committee on current developments and aspirations of the several 
programs of the Dental Health Activities of the Public Health Service. 

DIRECT RESEARCH 

The intramural research program of the National Institute of 
Dental Research is devoted to the development of effective methods 
for the prevention and control of dental diseases and related local 
and systemic conditions. The Institute's program is concerned with 
conducting and fostering investigations in fundamental oral biology 
as well as in matters directly relating to the causes, prevention, 
diagnosis and treatment of disease conditions of the oral cavity and 
its associated structures. The most prevalent of these conditions 
are dental caries, periodontal disease, bacterial and viral infections, 
and congenital anomalies. Because of the multiple and nonspecific 
etiology of many of these conditions, it is often necessary to isolate 
each of the various causal factors and study their effects alone, as 
well as in combination with each other. Such program objectives are 
achieved by the cooperative work of diversified scientific disciplines, 
including biochemistry, microbiology, genetics, oral pathology, 
histology, embryology and epidemiology. 

Undoubtedly, the most significant development in the history 
of preventive dentistry is the discovery in recent years of the oral 
health benefits related to fluoridation. Although dental caries is 
still a major health problem, each passing year sees progressive 
benefits to communities having fluoridated drinking water, However, 



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even in the face of this significant advance, efforts continue to 
be directed tov/ard the development of additional preventive measures. 
Recent and current research now provides substantial experimental 
evidence that an appreciable reduction in dental caries can be 
effected by dietary supplements of phosphate minerals. In addition, 
studies with germfree animals are providing important new information 
on the bacterial causes of dental caries, as well as on the relation- 
ship of the oral flora and various nutritional factors to calculus 
formation and the onset and progression of periodontal disease. 

Periodontal disease (pyorrhea), the main cause of loss of teeth 
in adults, continues to be a major research responsibility. Signifi- 
cant progress is being made in our understanding of this condition 
through the recent expansion of epidemiologic and biometric studies 
of selected population groups in this country and abroad. Such an 
approach has contributed information not only to the question of 
prevalence and severity, but also to the further development and 
testing of methods for assessment of this disease. In addition, 
basic studies are under way in the fields of oral bacteriology, using 
germfree animals to assess the cause and effect of tartar formation; 
and, in biochemistry to determine the nutritional and enzymatic 
relationships to periodontal disease. 

Fundamental research on cleft palate and other congenital 
anomalies involving growth and development of the facial region has 
long been a neglected area in dental as well as in medical research. 
These structural growth deformities are primarily an oral problem 
and there is a large diversity of professional interest involving 



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- 6 - 
the fields of maxillofacial surgery, orthodontia, prosthodontia, 
speech pathology and therapy, otolaryngology, psychology, and genetics. 
Gnotobiotic Program 

During the current year, gerrafree animals have been used to 
provide a controlled situation for testing the pathogenic effects of 
oral microorganisms singly and in defined combinations, and for 
evaluating the influence of constitutional and dietary factors on 
controlled disease processes. Unlike the great majority of infectious 
diseases, the lesions of tooth decay and periodontal disease harbor 
a variety of microorganims that are normally present in every mouth. 
Heretofore, it has not been possible to demonstrate the causal 
significance of any one organism or group of organisms. However, 
the Dental Institute's program in the germfree area has resulted in 
certain significant observations of sufficient importance to require 
reexamination and possible revision of present basic concepts ?e- 
garding the etiology of dental caries and periodontal disease. For 
example, in addition to our recently acquired knowledge that dental 
decay does not occur in germfree animals, even when they are main- 
tained on an otherwise caries producing diet, we are now able to induce 
extensive tooth decay in "germfree" rats when they are infected with 
a single strain of bacteria (a streptococcus) obtained from caries 
active animals. Since it is unlikely that a single organism is 
responsible for tooth decay, studies will be continued at the present 
level in order to discover the nature and contribution of other oral 
microorganisms to the caries process. 



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Another significant development in the Institute's gnotobiotic 
program is related to highly suggestive evidence that calculus (tartar) 
formation may occur in the absence of bacteria. Since such deposits 
are an important contributing factor to the development of periodontal 
disease, and have previously been thought to be due to microbial 
activity, this research activity will be vigorously pursued in the 
coming year. 
Nutritional Program 

A new approach to the control of dental caries is currently 
being explored by Dental Institute scientists in a cooperative study 
with other federal agencies and private institutions. This clinical 
investigation is based on the recently acquired evidence that dental 
decay in rats is dramatically reduced by adding a mineral phosphate 
to the diet. In large measure, this pronounced anticaries effect was 
achieved by incorporating dibasic calcium phosphate in the bread 
flour used to prepare the experimental diets. The fact that flour 
for human consumption may be "phosphated" has already been demonstrated 
by the widespread use throughout the Ration of self- rising bread and 
certain cake mixes which contain a similar compound. 

The presently operating clinical study is located in a number 
of selected children's boarding schools in South Dakota. With equal 
division into control groups and those which are receiving the mineral 
additive in the dietary, it is expected that annual examinations for 
the next several years will provide an indication of possible benefits 
to caries control. 



- 8 - 

Interest in this dietary experiment extends beyond the area 
of dental health. Inasmuch as the calcium as well as the phosphate 
content, of the children's diet is being increased, routine obser- 
vations on possible benefits to general health, and particularly bone 
development and body growth, comprise an essential part of the study. 
Experimental Caries Research 

During the current year, observations have been made which 
indicate that dental caries is an infectious and transmissible disease 
in hamsters and rats. These findings already have had widespread 
significance in the field of experimental caries research because 
they explain a number of phenomena involving resistance and suscepti- 
bility to caries that were formerly attributed to genetic factors and 
to systemic developmental effects presumably induced by diet and 
nutrition. 

On the basis of now completed studies, it is evident that the 
usual source of the caries producing microbial flora in young animals 
is from the alimentary tract of the mother; and that animals lacking 
this flora may acquire it by cross infection contact with caries active 
animals. However, while the cariogenic flora can be transmitted 
between members of the same strains, it is not ubiquitous in the 
general laboratory environment and may, in fact, require considerable 
time to become established at pathogenic levels. Work now in progress 
suggests that there may be limitations either in the extent to which 
the flora of one species can be transmitted to another, or in the de- 
gree to which it will be pathogenic if transmitted. This observation 



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may explain, in part, why previous attempts to induce caries in 
laboratory animals by the inoculation of non- indigenous (human) 
strains of bacteria have failed. 

Thus a significant contribution has been made in the current 
year which provides a firm basis for more definitive studies of factors 
influencing dental caries. 
Genetics Program 

Studies of hereditary defects in dental tissues, begun several 
years ago among isolated and inbred population groups in this country 
and Japan have been directed toward (1) a study of mechanisms of in- 
heritance of known hereditary diseases; (2) an evaluation of the role 
of heredity in other diseases not generally considered to be genetic; 
and (3) an elucidation of the underlying processes involved in hereditary 
disorders. 

It is hoped that recent advancements in our knowledge of the 
structure of chromosomes and genes, and the separation of spermatocytes 
containing different chromosomes, will open the way for newer methods 
of controlling or preventing hereditary disease. Additional objectives 
relate to the identification of those social patterns in our communities 
which influence the prevalence and distribution of intrinsic disease. 
Such knowledge would aid significantly in case finding and early 
diagnosis of genetic diseases during their incipient stages when they 
might be more susceptible to treatment. 
Epidemiology Program 

During the current year emphasis has been placed on the develop- 
ment and testing of field methods for the measurement of periodontal 
and other oral diseases in population groups. One important phase of 



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this program, conducted in collaboration with the Interdepartmental 
Committee on Nutrition for National Defense, has been to compare the 
prevalence of oral disease in individuals living under relatively 
civilized conditions with that of individuals in primitive villages 
of Alaska, Peru, Ecuador, and Ethiopia. Findings, to date, show a 
relative rarity of dental caries and periodontal disease in many of 
these primitive groups. 

Other projects receiving particular attention during 1960 have 
been the epidemiology of dental caries with particular attention to 
the fluoride-caries relationship; and an investigation of the influence 
of familial factors and of geographic location of periodontal disease 
and dental caries among Seventh Day Adventist families. The former 
program is providing evidence that caries inhibition is a simple 
function of the time available to a tooth for accumulation of fluorides 
prior to eruption, With reference to the latter study, a consistently 
low caries rate found in Adventist children may possibly be related 
to the dietary recommendation of the "health reform" suggested by 
the Adventist Church. 

RESEARCH GRANTS 

Increased funds in 1960 have provided for active program 
expansion in the following broad areas: (1) periodontal disease, (2) 
oral congenital anomalies (cleft lip/palate), and (3) dental caries. 
At the same time, emphasis was directed toward other important facets 
of dental research, such as oral-systemic interrelationships of chronic 
disease, electromyographic studies of the jaw, dental radiation in- 
vestigations, aging studies, and on dental public health research. 



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During this year, particular interest was focused on studies 
involving periodontal disease. Its etiology is virtually unknown; 
damage to the periodontal tissues is irreparable; and, treatment for 
this disease is empirical. Research investigations are now being con- 
ducted on dental calculus and its etiologic role, malocclusion factors, 
and contributing nutritional systemic relationships, as well as in 
basic studies involving the biochemistry, physiology, and morphology 
of the periodontal tissues. 

Research in cleft lip palate requires multidisciplinary co- 
operative effort on the part of both clinical and basic science 
researchers. Costly hospital and clinical facilities are required, to- 
gether with highly skilled and well trained personnel in several pro- 
fessions and specialities, New clinical projects designed for a co- 
ordinated attack toward solving some of the major problems in this 
field were initiated this year in university-affiliated hospitals and 
cleft palate clinics. 

While significant advances have been made in the control of 
dental caries, no single factor has thus far emerged as determinant 
in the etiology of this disease. During 1960 added support was given 
for bacteriological, salivary, and biochemical studies aimed toward 
filling gaps in the void of knowledge concerning this important oral 
disease. 

Other support during the year was programed for electromyographic 
investigations of masticatory structures because there is a strong 
indication that such information will go far toward solving some of 
the serious clinical problems of malocclusion, temporomandibular joint 



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dysfunction, and denture prosthesis. Increased support in FY 1960 
for radiation studies related to dental practice was another important 
aspect of the grants programs. Particular attention is now being 
directed toward aging studies, oral systemic chronic disease relation- 
ships, and broad studies of dental public health problems. 

FELLOWSHIPS 

The primary efforts of the research fellowship program are 
directed toward graduate training in the basic sciences with special 
emphasis on increasing the number of individuals trained in the basic 
sciences related to the study of periodontal disease, cleft palate, 
dental caries, and other oral diseases. In dental schools today there 
is a shortage of teachers trained in research techniques and as the 
schools broaden their curriculum and increase and modernize their 
research facilities, this shortage becomes more acute. Continued and 
increased use of the fellowship program is therefore necessary to 
staff the basic science departments and increase the research potential 
of the 47 dental schools throughout the country. The Institute, recog- 
nizing the need for competently trained personnel, has therefore, 
sought to support sound research training, to encourage training in 
certain critical fields, and to anticipate the demand for support from 
the growing number of graduate students. 

The research fellowship program as presently constituted is 
divided into four types of awards: (1) dental student part-time 
fellowships; (2) predoctoral fellowships; (3) postdoctoral fellowships, 
and (4) special fellowships. 



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Dental Student Part-Time 

The dental student part-time fellowship program is aimed at 
encouraging undergraduate dental students to give consideration to 
a career in academic dentistry and research. Analysis of the program, 
instituted in 1955, shows that a substantial number of students trained 
during the first five years have continued in academic dentistry and 
research. Currently, support at the level of eight units per school 
is available to all 47 dental schools. In 1961 the program will be 
extended to the schools of public health with at least two units to 
a school. By this means, dental students will be afforded the op- 
portunity of research experience during the summer period. 
Predoctoral 

Predoctoral research fellowships are awarded to qualified 
persons with a bachelor's degree who wish to undertake research in 
the fields of basic sciences related to dentistry. Such support also 
fosters the research- trained teacher program. 
Postdoctoral 

The objective of the postdoctoral program is to increase the 
number of dentally-trained personnel competent to conduct basic 
research as related problems of oral diseases. This program is a 
natural continuation of the dental student part-time program; experi- 
ence demonstrates that more and more of the part-time dental student 
fellows are applying for postdoctoral support following graduation. 
The increased funds made available for this program in 1960 are pro- 
viding for ten additional postdoctoral fellowships. 






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- 14 - 

Special 

Parallel with the increased number of dental researchers, the 
need for special types of training over and above the postdoctoral 
level has also increased, This type of award is made to the more 
advanced scholar and is especially beneficial to the investigator 
trained in a particular field who wishes to acquire a multidisciplinary 
approach often lacking in today's dental health research. Two 
additional special fellowships will be awarded this year. 

TRAINING 

The primary objective of the graduate training program is to 
increase the number of competent clinical researchers and/or teachers 
in dental schools and other dental research institutions throughout 
the U. S., thereby offsetting somewhat the current shortage of teacher- 
researchers presently available to these institutions. Increased 
physical facilities are now being built by many dental research 
institutions. Several new dental schools are projected during the 
next decade and each will require substantial numbers of additional 
personnel for research and teaching. 

There are three general kinds of training grants administered 
by the Dental Institute: (1) relatively larger grants for broad 
research training centers in a limited number of well-established 
dental research institutions, (2) grants to some schools to establish 
programs in only a single area of training because of certain special 
facilities in terms of research and personnel available, (3) smaller 
training grants to schools with less research and training potential 
to enable younger faculty members to go elsewhere for special training. 



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During 1960 progress in the area of training was seen in the 
establishment of seven additional research training centers and in 
supplemental support to expand current training programs. By the end 
of 1960, after only 3 years of program operation, twenty-five graduate 
training centers and other training institutions will be supporting 
approximately 130 trainees in both the basic and clinical sciences. 
Beneficial results from this modest but successful program are now 
seen in the some forty to fifty trainees who will complete their 
training in 1960. The great majority of these individuals will accept 
academic appointments when their training is completed. 

DENTAL PUBLIC HEALTH 

The Division of Dental Public Health, through its program of 
technical assistance, strives to prevent and control dental diseases 
through a series of integrated steps which may be viewed as a continuum. 

This continuum involves recognition of basic research discoveries 
which may have application in public health programs, further develop- 
ment or modification of such discoveries through applied technical or 
administrative studies, and the provision of consultation and technical 
assistance to States and communities in achieving rapid and extensive 
application of new and effective means of coping with the dental disease 
problem. Such consultaion, the major, continuing responsibility of 
this program, is provided by well-qualified staff in eight regional 
offices, 

Following are the major areas of activity identified with the 
technical assistance program. 



- 16 - 

Fluoridation 

The extension of the protection which fluoridation provides 
for the prevention of tooth decay continues to be a major goal of 
this activity. Slow but steady progress is evident in the complementary 
efforts of official and voluntary agencies and organizations to secure 
fluoridation of public water supplies. Currently, it is estimated that 
about one-third of the 100 million persons on public water supplies 
are receiving fluoridated water. The total national expenditure for 
community water fluoridation programs is approximately one-half 
million dollars. The tooth decay that is prevented by these programs 
would cost 50 million dollars to repair. This reduction in need for 
fillings makes additional chair time available for the treatment of 
other dental ills. 

The adoption of fluoridation throughout the Nation, however, 
remains a great challenge. For example, while a majority of the cities 
with populations of one-half million or more use fluoridated water, 
only 6 percent of the communities with populations under 2,500 are 
doing so.- Special emphasis is to be given in providing consultative 
technical assistance to these smaller communities. 

Although more than 35 million people in over 1,£50 communities 
served by public water supplies are now receiving the benefits of 
fluoridated water for prevention of decayed teeth, more than one-third 
of the population of the United States may never be able to enjoy these 
benefits because they consume water obtained from individual home water 
supplies. To meet this special need, a study has been implemented 
in 1960 to obtain data on the degree of acceptance and cost of providing 



- 17 - 

fluoridation to individual homes, and on attendant administrative and 
technical problems. Continuation of this study in 1961 will provide 
the necessary information upon which to evaluate the practicability 
of extending a home fluoridation system to families throughout the Nation. 
Health Practices 

It is increasingly evident that infectious diseases and chronic 
illnesses, including dental diseases, can neither be totally arrested 
nor prevented without the voluntary participation of individuals in 
necessary health practices. 

Increased attention is being given this year to the exploration 
of reasons why individuals accept or reject dental services and pre- 
ventive health practices, A study started in 1959 in New York State 
by the Division is in the late analysis stage. Another study has 
been completed regarding the acceptance of dental care by nursing 
home populations in Kansas City, Missouri. 

During 1960, limited studies of community response to positive 
health measures and practices have been initiated. It is hoped that 
a beginning can be made in setting up experimental situations to identify 
specific, important educational factors which are instrumental in 
changing people's dental health attitudes and behavior. These controlled 
situations will expose high school students to educational materials 
based on behavioral hypotheses which have emerged from the New York 
and Missouri studies. Analysis will be made of changes in the students' 
attitudes toward dental practices and actual changes in dental practices 
as a result of exposure to the different dental health educational 
materials. 



- 18 - 

Such studies potentially have very practical application. 
Information derived from them can help the administrator to develop 
programs which will motivate the greatest number of people to act in 
a way most conducive to preserving and improving their own health. 
Dental Auxiliaries 

The enormity of the dental health problem in the United States is 
further aggravated by the severe shortage of dentists to provide 
treatment for dental diseases. For the past third of a century, the 
supply of dentists in proportion to the population has been steadily 
shrinking. To increase the productivity of the dentist now in practice 
through expanded use of auxiliary dental personnel, a community-wide 
study is being undertaken to develop effective methods for the in-service 
training of private practicing dentists in the utilization of the 
chair-side dental assistant. Under the direction of a State health 
department, private dental practitioners will be trained in new and 
advanced procedures for utilizing assistants. Complementary training 
of assistants will be undertaken in conjunction with the instruction 
of dentists. This study is to be continued in 1961 far the purpose of 
appraising and improving the methods employed for training the private 
practicing dentist and assistant as a basis for more widely implementing 
such post-professional education programs throughout the Nation. 
The Chronically 111 

Studies were initiated during 1957 to develop specific information 
concerning the nature and extent of the dental service needs of the 
chronically ill and aged; to identify and solve technical and adminis- 
trative problems associated with making dental services available to 



'• . ' j 



■■'•X :i 



-- ' . ■■? 



- 19 - 

such persons; and to develop specialized equipment, clinical 
techniques and methods necessary for providing dental care services 
to these persons. These studies are being evaluated and preliminary 
findings have been prepared. During 1960 all patients participating 
in these studies are being placed on maintenance dental care. This 
will permit the staff to concentrate on organizing community re- 
sources to carry on the projects after completion of the study, and 
to evaluate the effectiveness of methods used to obtain community 
participation and interest in such projects. The applied research 
phase of this project will be completed by the close of 1961 at 
which time more will be known about applying and implementing this 
new knowledge in other communities throughout the Nation. 
Career Development 

During 1960 continued emphasis is being given to career 
development for Public Health Service dental officers by providing 
formal training in schools of public health and work experience in 
regional offices of the Service and in State health departments. 
Such training will help to insure a continuing supply of trained 
personnel for dental public health activities of the Service. 

DENTAL RESOURCES 
Although the American people today enjoy the highest standard 
of dental health in the world, it is a standard under which 60 percent 
of our people get no care at all within any one year and still others 
receive only the emergency services necessary for the relief of pain. 
Now, with the almost certain prospect that the better-educated citizens 
of tomorrow will seek a higher standard of dental health, there is the 



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i.'I- 



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juc •.■--Ji.'i 



■j:. ; i/"jft?'3 _• * j [/• 



i-lJ.i'-; '' •■, 



- 20 - 

serious possibility that the dental profession will be unable to 
supply services to all who seek them. 

Increases in dental supply have been lagging behind population 
growth for more than a generation. As a result, the number of dentists 
serving the civilian population has fallen from a previous high of 
58 per 100,000 persons to 46 today. Should all expansion in school 
capacity now planned be actuallyrealized, the number of additional 
graduates produced would still fail to halt the downtrend. Probably 
at best, today's schools can expand graduating classes to produce 
another 450 dentists per year. But to maintain the supply of dentists 
even at today's inadequate level--a level reflecting almost 30 years 
of steady decline--would require at least 2,700 additional graduates 
each year. 

One of the major functions of the Division is to assist States 
and regions in planning for needed school expansion. Completion of 
manpower surveys of the Midwestern and Mid-Atlantic states this year 
brought the total number of regional analyses of long-range manpower 
trends to six. The series now enjoys wide use by regional and state 
groups as a basis for planning and as models for similar studies 
of smaller areas. During the year, both the Western Interstate 
Commission for Higher Education and the New England Board of Higher 
Education took further action to implement the recommendations included 
in the Division's earlier studies of their region's problems. In 
New England a resolution reaffirming support of legislation permitting 
construction of new dental schools in Connecticut and Massachusetts 



::u 



- 21 - 

was approved by the Board. The Board further recommended the 
immediate establishment of Schools of Dental Hygiene in Maine and 
Rhode Island. In the West the Interstate Commission recommended 
to the Western governors the immediate expansion of all existing 
dental schools and the establishment of five new schools. More than 
a dozen states were developing plans for expansion or construction 
of dental and dental hygiene schools. 

These and similar activities designed to increase the number 
of dentists in practice are basic to all future dental health programs. 
Alone, however, they are not enough. A growth in the number of 
practicing dentists must be augmented by a major increase in dental 
productivity through greater efficiency in the use of the dentist's 
time. Such an increase depends not only on technological advances 
but also, and probably to an even greater extent, upon a more wide- 
spread and efficient utilization of the skills of auxiliary personnel. 
The Division's activities in this area were breatly accelerated. Its 
pioneer project to teach dental students how to work with dental 
assistants was doubled during the year. A January 1959 conference 
with dental school deans reviewed the initial three years of the 
project and discussed directions the project could profitably take 
in the future. In a new study, the Division began collecting data 
for an evaluation of the impact that various types of dental assistant 
programs now operated by these cooperating schools have upon attitudes 
and practice techniques of dental students, both during college and 
after they enter practice. 



-, -.-1 ■ ' • I 



i ■■-■ J-,:V 



- 22 - 

To provide a larger supply of better qualified dental assistants, 
the Division launched a new experimental program to determine the 
type and length of schooling required for their training. A cooperating 
junior college is offering two curriculums, one completed in a single 
year, the other completed in two, and on the basis of this dual ex- 
perience will make recommendations for a permanent, standardized 
training course. At the same time, a city school system will offer 
assistant training at the post-high school level in its public schools. 
To buttress this and similar experiments, another providing an on-the- 
spot study of tasks actually performed by assistants in private dental 
offices was initiated. 

As a corollary to activities aimed at increasing the availability 
of dental services, the Division studies all aspects of dental demand. 
One of the best indications of the increasing demand for dental care 
is the recent growth of pre- and postpayment plans. This growth 
heightens the need for dependable data on utilization patterns and on 
those factors serving as barrier or stimulus to the purchase of service. 
Intensified activity in studies of various types of dental payment 
plans has resulted in the publication of a variety of monographs and 
articles analyzing the salient features of the various plans. For 
example, one study was designed to analyze the attitudes dentists hold 
on the effects of a budget payment plan upon dental practice and 
patient's welfare. These findings were also related to actual utilization 
of the program by the dentists involved. Another study was begun 
this year concerning the participation and attitudes of members of 
Group Health Association Inc., with respect to that program's dental 
plan. 



- 23 - 

In conclusion, Mr, Chairman, the appropriation request for 
the Dental Health Activities in 1961 is a total of $11,204,000 as 
compared with the appropriation of $10,019,000 for 1960. This al- 
lowance for 1961 will provide for the continuation rf 1960 program 
levels in all activities and will permit some increase in grants 
for research projects and minor increases in the direct research 
activities which include $400,000 for equipment for the new dental 
building and $34,000 for clinical investigations. This request for 
1961 is distributed among program activities as follows; 
Grants ; 

Research projects ---------------$ 5,246,000 

Research fellowships ------------- 650,000 

Training 1,009,000 

Direct Operations ; 

Research _-- 2,021,000 

Review and approval of grants --------- 217,000 

Professional and technical assistance ----- 1,192,000 

Coordination & development of dental resources 774,000 
Administration ---------------- 95,000 

TOTAL 11,204,000 



SUMMARY OF OPENING STATEMENT 

Director, National Institute of Allergy and Infectious Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1961 ESTIMATE 

for 

'Allergy and Infectious Disease Activities" 



Mr. Chairman and Members of the Committee: 

The infectious disease activities of this Institute evolved from 
the earliest Public Health Service research. Allergy- immunology studies 
were assigned in 195&- 

Emphasis is placed upon the need for trained microbiologists, a 
central resource for all medical research. 

Upper respiratory diseases (a $3 billion medical bill and a $2 
billion annual loss to industry) represent an expanding field of study. 
Important causes of respiratory diseases, such as the parainfluenza viruses 
and viral agents in pneumonia, are being delineated. Vaccines are under 
development. Basic work on a number of microbial agents is also under way. 

The growth of allergy research, now emphasizing basic immunology and 
airborne allergens, is reflected in a two-year increase from 150 to 250 
grantee studies. Attempts are being made to standardize allergens employed 
by various investigators. 

Cystic fibrosis and staphylococcal infections are problems receiving 
special attention. The Institute is supporting a national survey to deter- 
mine the incidence and mortality of cystic fibrosis. Fungus diseases which 
develop in the wake of antibiotic or steroid treatment are also a growing 



- 2 - 
concern. A drug effective against skin fungus infections has "been 
developed. 

The Rocky Mountain Laboratory, Hamilton, Montana, and the Middle 
America Research Unit, Panama Canal Zone, investigate diseases of worldwide 
occurrence prevalent in their respective regions: Q fever and mosquito- 
borne encephalitides, for examples. 

As spokesman before Congress for the Gorgas Memorial Laboratory, 
Republic of Panama, the Institute Director requests the maximum funds 
authorized by made available to Gorgas. This amount is $250,000 for 
research and $250,000 for construction of additional facilities. 

The 196l appropriation request for the National Institute of Allergy 
and Infectious Diseases is a total of $3^,739,000. This compares with 
$3^,05^,000 for i960. The allowance for 1961 vail enable the Institute to 
maintain all activities at approximately the i960 program levels, and will 
permit an increase of $1,208,000 in research projects and minor increases in 
direct operations. This request for 1961 is distributed among program 
activities as follows: 

Grants : 

Research projects $22,777,000 

Research fellowships 1,066,000 

Training 2,709,000 

Direct • Operations : 

Research 7,l|-89,000 

Review and Approval 509/ 000 

Administration .,..<, 189,000 

Total 3^,739,000 



OPENING STATEIffiNT 

by 
Director, National Institute of Allergy and Infectious Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"Allergy and Infectious Disease Activities" 



Mr. Chairman and Members of the Committee: 

The infectious disease activities at the National Institutes of 
Health have evolved from the earliest Public Health Service research. 
Allergy-immunology studies were assigned in 195& as additional program 
responsibilities, and the National Microbiological Institute became the 
National Institute of Allergy and Infectious Diseases. 

The importance of this area of research is not restricted to the 
infectious diseases or allergic disorders. Scientists trained in micro- 
biology serve as a central resource for all of medical research. Their 
skills are vital to the pursuit of studies of cancer, neurologic diseases, 
cardiovascular disorders, and other major health problems. 

The noncategorical nature of microbiology and its importance as a 
"feeder" discipline are strikingly reflected in the scientific awards 
presented this year by the Lasker Foundation to honor outstanding contri- 
butions to medical research. All four of these distinguished prizes went 
to microbiologists- -men representing the fields of immunology, virology 
and epidemiology. One of the winners is Dr. Jules Freund, widely-imo\m 
immunologist, who is a staff member of this Institute. The significance 
of the work of these scientists cannot be assessed merely in terms of 



- 2 - 

infectious disease processes; it extends into and enriches all areas of 
medical biology. 

Thus, microbiological skills are a basic pre-requisite to progress 
in many areas of public health research; the need for trained microbiolo- 
gests is of paramount importance. 

Research Training 

High-quality medical research is the product of skilled, 
thoroughly trained, dedicated scientists. The demand for such people far 
exceeds the supply. The Nation must, therefore, recruit and train ade- 
quately motivated young investigators. This is a prime responsibility of 
a program such as that of the National Institute of Allergy and 
Infectious Diseases. 

Both the fellowships program and the training grants program of 
this Institute are helping to meet the need for specialized research 
training in the broad realm of microbiology, particularly with respect to 
allergy and immunology, infectious diseases, and tropical medicine and 
parasitology. 

A research fellowship permits a promising young scientist to secure 
needed training at a particular institution and under a particular mentor 
best fitted to his needs. He takes his own financial support with him. 
In 1958; 31 fellowships in the amount of ^113,000 were supported by this 
Institute. In i960 the number had increased to 223 with an allocation of 
^1,066,000. Only the most highly qualified students have been supported 



- 3 - 

by research fellowships from the National Institute of Allergy and 
Infectious Diseases. 

The training grant program provides funds not only to support the 
trainees but also to meet the institution's need for additional staff, 
equipment, and other items. In the 2 years that this Institute has had 
such a program, more than 80 research training units have been established 
or strengthened in the Nation's schools. A number of these are new pro- 
grams in allergy and immunology, an area where opportunities for research 
training have long been woefully inadequate. 

Acceptance of the Institute's training grant program by teaching 
institutions across the country is reflected in the rapid growth from 27 
grants amounting to §56k,91k in 1958 > the first year of operation, to an 
estimated 86 grants totaling $3*621,000 in I960. 

Upper Respiratory Disease 

More than 100 "new" viruses of man have been isolated since 19^-8 • 
They undoubtedly cause much of the upper respiratory disease responsible 
for about two-thirds of all our acute illness. The death of 20 million 
people throughout the world from the 1918 influenza epidemic underscores 
the fact that the respiratory disease problem cannot be equated simply 
with the "common cold" or other comparatively minor syndromes- -although 
these add to the general misery and multi-billion-dollar cost. 

Statistics indicating the impact on public health and economy of 
the respiratory diseases bear repeating: One million person-years lost 



- k - 

from work, housekeeping, or school during a 6-month period including the 
1957 Asian influenza outbreak . . . Approximately 28 k million acute 
respiratory illnesses serious enough to require medical attention in the 
United States during that epidemic year, ending in June, 195& 1 • • • An 
estimated 75 > 000 deaths associated with influenza in the same period . . . 
A $3 "billion medical hill and a $2 "billion estimated annual loss to 
industry due to the common respiratory diseases. 

Respiratory virus research has undergone a steady expansion in the 
last several years as increased funds became available both under the 
research grants program and the Institute's direct operations. Much of 
the recent progress in this area relates in some degree to the higher 
support levels which characterize infectious disease research today. 

In the virtual absence of effective drugs against viruses among 
hundreds of compounds tested, the objective is prophylaxis through new or 
improved vaccines. A prototype of such biologies is the adenovirus 
vaccine first developed by this Institute in 1955 an <i shown through our 
studies and those of the Ualter Reed A^y Institute of Research to be 
effective in reducing respiratory disease in recruits. This is now being 
produced cOi.imercially and the military has prepared plans and specifica- 
tions for routinely administering adenovirus vaccine. 

A striking example of the importance of knowing which viruses we 
are dealing with is provided by continuing epidemiological work on the 
hemadsorption viruses, first isolated by scientists o± this Institute and 



- 5 - 

Children's Hospital, D. C, in January 19^8. These cell-parasites, now 
called parainfluenza viruses, were round responsible for 20 percent of 
the respiratory disease in large groups of children at three Washington, 
D. C hospitals. In contrast, Asian influenza --and this was during its 
epidemic year- -caused only 13 percent of the respiratory disease in the 
group. Since the newly isolated viruses caused symptoms that closely 
resembled those of Asian influenza, one could reasonably conclude that 
some cases of Asian influenza attributed to vaccine failure actually were 
caused by the newly recognized viruses. Work is under way on a vaccine 
against the parainfluenza group and other "new" viruses which cause 
respiratory disease. If an effective biologic can be developed, it might 
be combined with influenza strains in a polyvalent vaccine. 

The new parainfluenza virus has also been isolated (in studies by 
this Institute and USDA's Agricultural Research Service) from cattle 
afflicted with shipping fever, a costly respiratory illness. Although 
our primary interest is public health, veterinary medical advance should 
be a valuable by-product of this research. 

The atypical or viral pneumonias represent another serious clinical 
problem in the respiratory field. A recent large-scale study in Marine 
recruits has revealed that the Eaton virus (first isolated by Dr. Monroe 
Eaton of Harvard) may be an important cause of non-bacterial penumonias 
in military recruits. In this epidemiological work, the Institute co- 
operated with the Navy Bureau oi' Medicine and Surgery and the Naval 



- 6 - 
Medical Research Unit at Camp Lejeune Marine Base, and with the Walter 
Reed ..rmy Institute or Research. The relatively new technique of lagging 
antibodies with fluorescent dye, which has proved so useful in quickly 
identifying "strep" infections, was employed in these investigations. The 
study is particularly important because it indicates a considerable involve- 
ment of the Eaton virus in a type of pneumonia not previously linked with 
a causative agent. Atypical pneumonia is often a serious clinical disease; 
a vaccine might be warranted. The work is being extended to include more 
than 1,000 new recruits at the Marine base. 

Respiratory-related virus studies, ranging from work employing the 
tobacco mosaic virus variant -system to elucidate the chemistry of mutation 
(University of California) to observations of gene transfer by the phage 
viruses that parasitize bacteria (University of Colorado) are a part of 
our over-all research grants program in virology, which totals $3 million. 
Many investigations under this program are directly related to clinical 
respiratory disease. For example, Institute grantees at Harvard, Boston, 
and Tufts university medical centers reported last spring on findings in 
Asian influenza-associated fatalities. Their studies re-emphasized that 
pregnant women and people with chronic heart disease or chronic respira- 
tory insufficiency are particularly susceptible to severe influenzal 
disease and are prime candidates for immunization. 

. J.lei-gy-Immunology 

rvn extensive urban survey of major allergies, conducted by a group 
of New York investigators and reported at the 1959 annual meeting of the 



- 7 - 

:<jnerican College of Allergists, revealed these disorders to be twice as 
prevalent in the general population and four times as prevalent in children 
as previous estimates for the Nation had indicated. No small amount of 
this illness is disabling and sometimes fatal. Crippling lung insuffi- 
ciency from chronic asthma, and anaphylactic shock after drug injection 
are examples of serious allergic sequalae . 

An Institute immunologist employing facilities of New York Univer- 
sity has shown that susceptibility to the form of brain damage known as 
allergic encephalitis can be passively transferred from a sensitized and 
susceptible rat to a normal rat by injection of lymph node cells from the 
former. This will provide a useful model for studies of this allergic 
mechanism which has a counterpart in man, for example, in the occasional 
paralysis following vaccination against rabies. 

The National advisory allergy and Infectious Diseases Council in 
1959 held a scientific conference on allergen standardization attended by 
30 of the Nation's foremost research immunologists. Out of the conference 
came coordinated assignments designed to standardize ragweed pollen 
extracts as a model system. Scientific investigators must have allergenic 
products meeting rigid norms of potency, purity and specificity. 

The growth of the allergy research program, first established in 
the Public Health Service ^!- years ago, is reflected in an increasing number 
of research project grants. Approximately 150 studies totaling $2 million 
were supported by the Institute in 1958- In i960 support will approach §k 
million for about 2^0 allergy-immunology grants. 



- 8 - 

Grantees at the University of California have shown, for example, 
that mice subjected to stress have an increased resistance to allergic 
shock- -a finding pertinent to investigations of the effect of environment 
on susceptibility. In another study at Bellevue Medical Center, New York, 
researchers are using radioactive isotopes to "label" allergens so they 
can follow what happens during an allergic reaction in the skin. Many 
industrial allergies are manifested in skin conditions. Ragweed pollen, 
the most prevalent plant allergen in the United States, is also being 
tagged by isotopes deposited in the plant. The grantees, working with the 
aid of the Brookhaven National Laboratories, are attempting to trace, with 
Geiger counters, the routes and distances travelled by the radioactive 
pollen . 

C ystic Fibrosis 

In compliance with last year's Congressional request for more 
accurate figures to outline the dimensions of the health problem presented 
by cystic fibrosis, the National Institute of Allergy and Infectious 
Diseases made available a special grant to the Children's Bureau and the 
National Office of Vital Statistics for this purpose. Recently, these 
agencies completed the first phase of their hospital survey, revealing 
that approximately 2,500 cystic fibrosis patients, 95 percent under 20 
years of age, were discharged from or died in hospitals during 1957* 
Fatalities in the group numbered 359> °r 1^- percent. The survey team 
emphasized that these figures represent only a fraction of the total 



- 9 - 

number of children suffering from cystic fibrosis. The University of 
Nebraska, for example, reported kO children under treatment for this disease; 
only k in this group had teen hospitalized. 

The statisticians and medical scientists on the project are now 
engaged in outlining methods to enlarge the survey by conducting a national 
epidemiologic study of the disease. One of the more serious obstacles they 
face is the absence of a simple diagnostic test for determining the presence 
of the disease in the child. Currently the two methods considered most 
reliable are duodenal intubation and the sweat test. Both, however, present 
certain disadvantages. Scientists of our Laboratory of Clinical Investiga- 
tion have been working for some time to solve this problem by developing 
the diagnostic possibilities inherent in a simple blood test and a large- 
scale investigation of this method is currently under way. 

As a direct reflection of Congressional interest in this relatively 
new disease, our program has undergone a rapid expansion during the past 2 
years. For fiscal year i960 a total of $350>000 was allocated "co continue 
studies aimed primarily at solving the severe problems of the secondary 
infections attending this disease. Much of our initial progress in mobiliz- 
ing against cystic fibrosis stems from this increased level of support both 
for this Institute's program and complementary studies in the National 
Institute of Arthritis and Metabolic Diseases. 

It may also be added that the studies now in progress on staphylococ- 
cal infections have a special pertinence to cystic fibrosis. While the 
underlying defect in this disease is genetic in nature, the most critical 



- 10 - 

problem is the control of pulmonary infections to which these children are 
especially susceptible. In one cystic fibrosis study involving 3^0 
fatalities, it was shown that more than 9° percent occurred directly as a 
result of chronic lung disease whose most striking feature is its associa- 
tion with the staphylococcus agent. Thus it is clear that cystic fibrosis 
patients will be the direct beneficiaries of anjr progress which science is 
able to make against these widespread and persistent infections. 

Staphylococcal Infections 

The development of antibiotic-resistant strains of staphylococcus, 
together with their widespread dissemination through hospitals and communi- 
ties, continues to represent a -public health problem of highest priority. 
In terms of morbidity and mortality, impact on other diseases, increased 
costs of medical care, and special hazards for all hospital patients, the 
staphylococcal problem is so well documented as to need little elaboration. 

IJhat should be emphasized is the fact that this is not a phenomenon 
peculiar to this species of bacteria. Rather, it is a problem which cuts 
across a broad biologic front. 

Most pertinent to this view is a warning issued by one of our grant- 
supported scientists who recently reviewed patient records spanning a 2k- 
year period at Boston City Hospital. It was his conclusion that the 
favorable impact of the antibacterial drugs in reducing the number of 
deaths from the pneumococcal pneumonias aud streptococcal infections has 
now been more than overshadowed by an increase in deaths from staphylococ- 
cal disease and from infections by other bacteria once considered 



- 11 - 

relatively harmless. 

Because of the findings of this and similar studies, the problems 
relating to antibiotic resistance are now regarded as the most immediately 
urgent confronting hospitals. Scientists of this Institute are now attach- 
ing this problem in studies designed to uncover basic knowledge of bhe 
precise mechanisms by which the staphylococcus is able to produce disease 
and resist therapeutic assault. One of the more fundamental of these 
continuing studies in our Laboratory of Bacterial Diseases was devised to 
furnish exact data on the degree of virulence which may be induced by 
specific quantities of the standard staphylococcus strains, with the view 
to using this information as a baseline for immunization tests. 

In another study of the coliform species of bacteria, our scientists 
have withdrawn, from the inner portion of the cell, certain of the soluble- 
constituents containing the enzymes responsible for energy formation and 
use. When these energy-forming systems were taken from susceptible strains 
of the coliform species, they were shown to be inhibited in the presence o± 
an antibiotic. This was not true for resistant strains. Such an experi- 
ment pinpoints the particular locus of resistance in certain bacteria and 
hopefully may lead to a prototype definition of the resistance mechanism 
in general. 

Our accelerated grants program, increased by $1 million in 1959 
over previous levels and continued at this rate during the current year, 
is now beginning to yield initial results. Much of the information being 
received is e. .tremely fundamental, due to the poorly explored nature of 



- 12 - 

the subject under study. An an example, the research undertaken by one of 
our grantees at the University of Colorado Medical Center has described a 
plausible means by which resistance may be transferred to sensitive bacteria. 
In a series of complex experiments, he has found evidence that certain of 
the phage viruses which are known to parasitize bacteria may pirate the 
resistance mechanism from one strain of staphylococcus and transfer it to 
members of a strain previously susceptible to antibiotics. 

Fungus Diseases 

The growing realization that any great advance in the treatment of 
disease is likely to introduce new medical problems arising out of man's 
efforts to adjust to changes in his social and physiological equilibrium 
is nowhere more clearly illustrated than in the rising incidence of fungus 
disease. A recent study analyzing some aspects of hospital experience with 
microbial infections today as compared with a period immediately preceding 
the introduction of antimicrobial drugs reveals that fungus infections, 
previously of little consequence as a cause of fatality, have now risen to 
fourth place just behind the staphylococci, viruses and gram negative 
bacilli. In many cases, fungus infections are superimposed on other 
diseases initially prompting hospitalization. In view of this, the 
National Institute of allergy and Infectious Diseases has undertaken to 
strengthen its program in order to define more clearly the role of fungi 
in human disease. 

Findings include the recent disclosure by our laboratory scientists 
of an intimate association between the house bat and the agent of 



histoplasmosis, a pulmonary disease which may closely parallel the early 
manifestations of tuberculosis. In another study our scientists have shown 
that contact with pigeon droppings may result in a severe form of fungal 
meningitis. The pigeon itself is not infected, tut its droppings serve as 
an excellent culture medium for the airborne spores of the fungus. 

This Institute has long supplied leadership in epidemiological 
studies of fungus disease. Such investigations are now being extended into 
clinical medicine through joint studies of our laboratory scientists and 
clinical investigators. Their varied research activities include a 
special pursuit of the possibilities of immunization against these diseases 
and complete clinical trials of various drugs developed as curative agents. 

Until the introduction of a new drug, amphotericin B, a i'ew years 
ago, most patients afflicted with the serious disseminated forms of fungus 
infection were compelled to struggle through the natural course of the 
disease without the aid of an effective chemotherapeutic agent. Clinical 
trials undertaken by our scientists in 1957 helped establish the usefulness 
of this drug against certain of the serious systemic forms of these infec- 
tions. Our laboratory scientists are continuing their search for new 
drugs for the deeper fungal infections . 

Perhaps the most encouraging immediate development to emerge from 
the expanded program of fungus studies supported by the National Institute 
of JJLergy and Infectious Diseases in vari.ous private institutions is the 
recent introduction of systemic treatment against the superficial x'ungus 



- Ik - 

( ringworm) infections. During the past year, our grantees at the University 
of Miami School of Medicine announced that griseofulvin, administered 
orally to patients with a wide variety of typical ringworm infections, pro- 
duced highly favorable results. Infections of long duration, up to 60 years 
in one dramatic case, proved as susceptible to treatment as those of only a 
few weeks' duration. Griseofulvin, under the trade names, Fulvicin and 
Grifulvin, has now been licensed for manufacture by Schering and McNeill 
Laboratories. 

Rocky Mountain Laboratory 
Historically noted for the conquest of Rocky Mountain spotted fever, 
this field laboratory in Hamilton, Montana is today a modern two -million - 
dollar research center. The main emphasis is upon diseases important to 
the Western region of the United States, but many of these are also of 
world-wide importance. With the continuing expansion of the work of this 
Laboratory on behalf of the western states and the Nation, animal experi- 
mentation, particularly with regard to diseases that in nature are trans - 
metted from animals to man, has increased materially. Q, fever, Colorado 
tick fever, tularemia, and equine encephalitis are examples of infections 
of this type. In i960 Congress provided f' 150,000 for construction of ade- 
quate animal facilities. Work is now under way on these, with foundation 
poured and superstructure erected. The productivity of the Rocky Mountain 
Laboratory investigators is reflected in the scientific literature. Some 
of these recent research reports --on the epidemiology of influenza in an 



isolated community, the growing hazard of Q fever, overwintering Ox Western 
equine encephalitis virus, dissei.iination of rabies, reservoirs of Colorado 
tick fever virus in nature , epidemiology of shi ellosis, tularemia surveil- 
lance ^ and other findings are summarized in the "research highlights'' 
accompanying this statement, 

Middle America Research Unit 

Studies of arthropod-home virus infections continue to represent 
the major emphasis of the Middle America Research Unit, which was established 
'd years a^o in the Canal Zone. The Unit's virus studies were broadened in 
the past year to include surveillance of the live poliovirus vaccine 
(Lederle) program conducted by the Ministry of Health of Costa Rica under 
PAHO-WHO sponsorship. Other virus projects include encephalomyocardi.tis in 
swine and human epidemic influenza. 

The Mycology Section of MARU, staffed by the Walter Reed Army 
Institute of Research, has been extending its worl: on histoplasmosis, 
particularly with reference to the significance of this fungus infection to 
military personnel stationed in an area of historic histoplasmosis 
endemicity. 

When MARU was co-sponsored in October 1957 > by the NIH and WRAIR with 
the cooperation of Canal Zone officials, provision was made ±01- scientific 
evaluation of the program after 2 years of operation. An ad hoc committee 
selected for scientific and administrative competencies pertinent to the 
mission conducted extensive studies, including site visits, and recommended 



- 16 - 



that MARU should continue as a permanent field station of the Public Health 
Service . In its endorsement, the Committee commended the Director. of MARU, 
Dr. Alexis Shelokov, for the excellent scientific organization he has 
created in a short time; pointed out that considerable planning underlies 
selection of the most worthwhile projects from an abundance of opportunities , 
recognized that occasional diagnostic service will be necessary but recom- 
mended that service should be carried out only as directly related to 
laboratory research; suggested a joint scientific advisory board for MARU 
and Gorgas Memorial Laboratory, and envisioned more specific bi-lateral 
agreements on MARU between the National Institutes of Health and the Pan 
American Sanitary Bureau. 

At Bethesda, the MARU- correlated unit on arthropod-borne viruses is 
obtaining and stocking viruses and their diagnostic reagents for the 
Laboratory of Tropical Virology. Over 150 arthropod-borne viruses are now 
recognized. Most extensively studied by the Canal Zone group and its 
Bethesda counterpart is the virus of Eastern equine encephalitis. This 
disease is seen in the United States during sporadic epidemics notable for 
a high fatality rate, such as the 1959 outbreaks in the New Jersey area. 
Most of the arthropod viruses are carried by mosquitoes. Diseases caused 
by these viruses still are x^oorly differentiated, but represent a consider- 
able threat to public health in temperate as well as tropical areas 
throughout the world. Yellow fever, one of the arthropod-borne group, is 
under intensive study by the Gorgas Memorial Laboratory in the Republic of 



- IT - 

Panama, with MARU providing some technical assistance as requested. 

The Gorgas Memorial Laboratory 

The Gorgas Memorial Laboratory in the Republic of Panama is the 
medical research unit of the Gorgas Mmeorial Institute of Tropical and 
Preventive Medicine „ The Laboratory is an outpost for research on yellow 
fever, malaria and other diseases endemic to Middle America and presenting 
potential problems to adjacent areas and the United States. Jungle yellow 
fever, for example, is advancing northward from South and Central America 
at an average of 13 miles each month. The conditions which permit this 
resurgence are under study. Gorgas scientists are exploring outbreaks of 
encephalitis of types sporadically epidemic in the United States, as well 
as the over-all area of arthrox^od-borne infections. They recently reported 
the isolation of St. Louis encephalitis virus in Panama from human blood 
and naturally infected mosquitoes- -the first recovery of the virus in 
Middle America. 

Gorgas investigators are also developing new information on Chagas' 
disease and leishmaniasis. Sandflies of the man-biting Phlebotomus species 
have now been artifically infected with leishmania in attempts to reproduce 
this disease in laboratory animals which will then be used to screen for 
better drugs . 

On September 21, 1959; Public Law 36-296 authorized increasing the 
annual appropriation from $150,000 to $250,000, and also authorized $250,000 
for construction of additional facilities on land valued at over a 



- 18 - 

quarter-million dollars already in possession of Gorgas, a gift of the 
Republic of Panama. A more extensive discussion of the research accomplish- 
ments and mission of the Gorgas Memorial Laboratory , now in its 31st year, 
is available in the Committee print on the Hearing relative to this increase, 

Dr. Walter A. Bloedorn, President of the Gorgas Memorial Institute, 
has submitted a copy of the operating budget for the Gorgas Memorial 
Laboratory. They will be able to make good use of the total amount author- 
ized. Primarily, they wish to increase the staff, rehabilitate the power 
supply and plumbing systems, develop more space for small animals, and pro- 
cure equipment to provide for the added staff. 

As spokesman for the Institute before Congress, I am requesting that 
the maximum funds authorized by Congress be made available to the Gorgas 
Memorial Institute of Tropical and Preventive Medicine during 1961. 

Support of Institute Programs 

The 1961 appropriation request for the National Institute of Allergy 

and Infectious Diseases is a total of $3^> 739; 000. This compares with 

$3^ ; 05^, 000 for i960. The allowance for 1961 will enable the Institute to 

maintain all activities at approximately the i960 program levels. This 

request for 1961 is distributed among program activities as follows: 

Grants : 

Research projects ^£^,777>00° 

Research fellowships 1,066,000 

Training 2,709, 000 



- 19 



,/ 



Direct o perations : 

Research 7,1*89,000 

Review and Approval 509,000 

Administration 189, 000 

Total 3^,739,000 



SUMMARY OF OPENING STATEMENT 

by 

Jirector, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"Arthritis and Metabolic Disease Activities' 1 



Mr. Chairman and Members of the Committee: 

The 1961 budget request for Arthritis and Metabolic Disease Activi- 
ties which is before you is for $4-7,54.1,000 as compared to the appropriation 
of ^6,862,000 for I960. 

This year, I960, marks the tenth anniversary of the National Institute 
of Arthritis and Metabolic Diseases. It has been a ten year period of 
remarkable growth, highlighted by advances in both the basic sciences 
and in clinical medicine. 

In the rheumatic disease field the Institute is supporting a con- 
siderable amount of research on hypersensitivity as a possible cause of 
rheumatoid arthritis, and this research effort is showing increasing promise. 
In gout treatment, new and better drugs are now available and we have been 
able to further clarify the basic nature of this disorder. Diabetes research 
continues to feel the impact of the oral antidiabetic drugs and possible new 
uses for them have been discovered. Accomplishments in basic research were 
highlighted this year by the awarding of the Nobel Prize in medicine for 
work done on the synthesis of nucleic acids. One of the recipients was 
a former chief of one of our laboratories and the other was a grantee of 
the Institute. 



n :■■?• '', 



* 



In addition to strengthening the research and training programs 
in all our areas of responsibility, we are vigorously extending our 
efforts in newer fields of interest such as cystic fibrosis, gastro- 
enterology and international nutrition studies. 

The appropriation request for 1961 represents an increase of 
?679,000 over the appropriation of M.6,862,000 for I960. This allowance 
for 196l will provide for the continuation of I960 program levels in all 
activities and will permit some increase in grants for research projects 
and minor increases in direct research activities, principally in cystic 
fibrosis, gastroenterology and nutritional research under germfree 
conditions. This request for 1961 is distributed among program activities 
as follows: 

Grants: 

Research projects • J> 2,153 000 

Research fellowships 437 000 

Training grants 6,291,000 

Direct research and supporting services ■ -8,653 ,000 

Total 47,541,000 



OPENING STATEMENT 

by 

Director, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 
COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"National Institute of Arthritis and Metabolic Diseases' 1 

Mr. Chairman and Members of the Committee: 

This year, I960 marks the tenth anniversary of the National 
Institute of Arthritis and Metabolic Diseases. It has been a ten- 
year period of remarkable growth, highlighted by advances in both the 
basic sciences and in clinical medicine. At this time, and before we 
move into the ne:-:t decade , I should like to review with the Committee 
some of the accomplishments of these first ten years, and describe to 
you the excellent progress made during this first decade in three areas 
of special interest, rheumatic diseases, diabetes and basic research - 
metabolism. The second portion of this statement describes the new 
developments of the current year, the new areas into which our scientists 
are now extending their vigorous efforts, particular attention being 
given to cystic fibrosis and gastroenterology. 

The advances to be described have resulted from work done both in 
our own laboratories in Bethesda and in the many non-governmental 
institutions throughout the country receiving support from this Institute 
in the form of research grants, training grants, traineeships and 
fellowships. 



RHEUMATIC DISEASES 

Ten Years of Progress . Only slightly more than ten years ago, 
just prior to the momentous discovery of cortisone 's effects and the 
establishment of the Institute, the rheumatic disease field was one of 
the most neglected areas in medicine. For hundreds of years there had 
been little real progress either in the understanding or in the treatment 
of these diseases, although they affected an estimated ten million people, 
Most physicians shared the sentiment once expressed by the great 
Dr. : Jilliam Osier — "'When an arthritic comes in the front door, I want 
to go out the back door . '■ 

There was no specific form of therapy for these diseases and 
relatively little was being done for sufferers from them. Of the entire 
number of beds available in university hospitals throughout the country, 
there were only 700 beds usually occupied by arthritics. At that time, 
the total amount of money spent on research in the rheumatic diseases 
was only $300,000, and this included both government and non-government 
funds. Of this .^300,000, one- third was going to only three universities. 
There was little clinical training of young physicians. Only eight 
centers in the United States had well defined training programs in this 
area. 

Contrast this discouraging situation with the very hopeful one 
that exists today. Under the auspices of this Institute alone over 
^4,000,000 is being devoted this year to rheumatic disease research. A 
tremendous increase has occurred in the amount of professional training 



- 3 - 
being carried on, primarily as a result of the Institute's traineeships 
program and training grants program. The traineeships began in 1953 
when the Institute supported 21 arthritis trainees in 14 different 
institutions. Today, we are supporting 92 trainees in over j+0 institu- 
tions. Also, due to the important activities of the Arthritis and 
Rheumatism Foundation there are now more than 300 arthritis clinics 
throughout the country. 

New Forms of Treatment a As has been discussed with the Committee, 
cortisone was first used in 1948 to treat patients with rheumatoid 
arthritis. Since that time the pharmaceutical industry has developed a 
whole spectrum of anti-inflammatory steroids. Continual modifications 
of the original cortisone molecule has produced drugs that are not only 
more potent than cortisone but also have less tendency to produce serious 
side effects. During the past ten years many of these industry -developed 
compounds have been tested in our Clinical Center at Bethesda and have 
largely replaced cortisone. 

It must be remembered, though } that these powerful new drugs may 
make arthritics more comfortable 5 but they are not curing the underlying 
disease. In many cases, the disease process continues even though the 
pain has been relieved. It is for this reason that we believe basic 
laboratory research is vital. We have yet to find the cause of the 
rheumatic diseases and until we do it is quite unlikely that we will 
be able to develop a specific curative agent. 



4 - 

For the past ten years the Institute has placed heavy emphasis 
on basic research, both intramurally and extramurally > and we have 
witnessed some very promising developments in the rheumatic disease field. 
For example, we now know many of the biological details of these diseases, 
not only how they affect the functioning of whole systems within the body 
but also how they affect individual cells, causing subtle but very 
important changes in metabolic processes. Solid advances have been made 
along many fronts but I would like to mention one in particular, 
albeit a very broad one, that relates to our search for the basic cause 
of arthritis. 

Arthritis and Hypersensitivity . Studies over the past ten years 
have more and more clearly pointed to the possibility that rheumatoid 
arthritis has an immunologic basis, and results from a state of hyper- 
sensitivity. This implies that individuals develop the disease when 
they become overly sensitive to substances within their body, possibly 
to their own altered protein. Rheumatoid arthritis may therefore be a 
disease of autosensitivity . 

Fragmentary support for this theory has come from both clinical 
and pathological studies. Especially interesting is the research on the 
rheumatoid factor, a substance found in the serum of patients with 
rheumatoid arthritis and one that is peculiar to these patients. The 
rheumatoid factor has already been made use of as a diagnostic tool, 
being the substance that is detected by various diagnostic tests 
developed in part in our own laboratories and by our grantees. 



•■ 1-. 



- 5 

It has now been shown that the rheumatoid factor, or more 
correctly rheumatoid factors, are gamma globulins and have many if not 
all the characteristics of antibodies — protein substances that provide 
variable degrees of immunity to particular diseases. The presence of 
such antibodies in rheumatoid arthritis presents the intriguing possibility 
that there is some antigen present, some deleterious substance to which 
the body is sensitive and to which it responds by producing antibodies. 
To be sure, we have not yet been able to find the specific antigen, and 
until we do, its existence must continue to be regarded as speculative. 

There are many substances in normal body cells which could 
possibly be antigenic. If they are in fact the antigens , then the 
disease may result when some defect in body metabolism causes an over- 
sensitivity to these normal substances. Another possibility is that 
the substances might become antigenic only under certain conditions, or 
after undergoing certain alterations. 

Not too many years ago, classical immunological theory had no 
place for such a concept as autosensitivity . We now know, however, that 
auto sensitivity is indeed possible and have actually recognized it as 
the cause of two diseases, one in which a person becomes sensitive to 
his own thyroid hormone, and another in which one becomes sensitive to 
his own red blood cells. 

In the past several years the tempo of research in this area of 
hypersensitivity has increased considerably, and more and more scientists 
are becoming involved. Notable contributions have been made by 
Dr. Henry G. Kunkel, a grantee of ours at the Rockefeller Institute, who 



• 6 * 
was the first to determine the exact size of the rheumatoid factor 
molecules. The work of another Institute grantee, Dr. Morris Ziff , has 
provided additional evidence supporting the sensitization theory. 
Dr. Ziff has studied the families of patients with rheumatoid arthritis 
and found that the rheumatoid factor occurs in many of the healthy 
relatives of the patients as well as in the patients themselves, thus 
suggesting that some hereditary metabolic defect is involved. The work 
also suggests ; however, that a second abnormality is present, since not 
all persons with the rheumatoid factor have clinical symptoms of the 
disease. 

In other Institute- supported studies of the rheumatoid factor, 
scientists at New York's Hospital for Special Surgery and the Wilson 
Research Foundation have found that the factor is produced in two kinds 
of cells; plasma cells, present in the lining of human joints, and 
''large pale cells" in the body's lymph nodes. This marks the first time 
that the rheumatoid factor has been identified in human tissue. 

There are many aspects of the problem that are indefinite, however. 
Primarily> it is still uncertain that the rheumatoid factor is an antibody. 
If it is an antibody, the specific antigen which causes its production 
must be identified and it must be determined whether or not it is the 
actual cause of the disease or merely a by-product. 

These are the problems that confront us on the road of sensitization 
research, as a possible cause of the rheumatic diseases. It is an 
increasingly exciting road, but there is certainly no assurance that it 



■- i ^:.">rr 



7 
is the right one. None the less, much of the recently uncovered evidence 
strengthens the possibility that immunologic mechanisms are somehow 
importantly involved. 

Advances in Gout Treatment . The past ten years have also witnessed 
major advances in the understanding and treatment of gout, another of the 
rheumatic diseases. This ailment has plagued man for at least 4,000 
years and affects approximately 30-.000 persons in this country. Usually, 
the first sign of the disease is painful swelling in one of the joints 
of the body } mere frequently than not that of the big toe. These attacks 
of gouty arthritis generally subside after days or weeks, although they 
recur at irregular intervals throughout the victim's life. 

Associated, but in an unknown fashion, with these acute attacks 
is a disturbance in body chemistry which results in an increase in the 
amount of uric acid in blood and tissues. The uric acid is often de- 
posited in cartilage, and in time forms large masses of chalky uric acid 
salts. These deposits are known as tophi and may appear around almost 
any joint. 

The treatment of gout has centered around the use of two different 

types of drugs, one type to overcome the acute attack of pain and swelling 

and the other type to lower the uric acid concentration in the body. For 

the acute attack, the most specific drug is colchicine, which has been 

used for thousands of years. Several years ago Institute studies showed 

r 
that the drug is more promptly effective when injected rather than given 

orally. It is also less likely to cause undesirable gastrointestinal 

effects when injected. 



- 8 - 

Steady improvements have also been made in the uricosuric drugs., 
those which are used in the long-term treatment of gout patients and 
promote the urinary excretion of excess uric acid. Two of the most 
potent ones now available are zoxazolamine and sulfinpyrazone, both of 
which have undergone clinical testing at the Institute. These drugs are 
not useful in treating the acute attacks and must be supplemented with 
such a drug as colchicine. Used properly, however, they are of great 
value in preventing crippling. 

Basic research in gout has now shown that the primary metabolic 
defect in many gout patients is the overproduction of uric acid. This 
has been a controversial question for many years, since the excess acid 
might also have resulted from insufficient destruction of the substance 
within the body, or the inability to excrete it in proper quantities. 

Institute studies with an experimental drug known as DON indicate 
that it may be possible to slow down the body's overproduction of uric 
acid by drug therapy. The experimental compound blocks an enzyme needed 
by the body for the synthesis of uric acid. At present, the drug has 
little practical value since it causes undesirable side effects, but 
it demonstrates that excess uric acid production can be reduced. 
Research is continuing on similar drugs which will duplicate DON's action 
without causing any ill effects. 

DIABETES 

A Problem in Basic Research . The greatest single achievement in 
the study of diabetes was undoubtedly the discovery of insulin, an- event 



- 9 - 

v/hich took place long before the Institute was established. To 
appreciate its importance, one has only to remember that prior to the 
first use of insulin in 1922 the disease in its more serious forms 
proceeded almost inevitably into acidosis, coma and death. Today . the 
life expectancy of the diabetic is almost as long as that of the non- 
diabetic. 

As has been discussed previously with this Committee, diabetes is 
probably the best known and most important of the metabolic diseases. 
It results from either an insufficient production of insulin by the 
pancreas, or from interference with insulin's action after it has been 
produced. Because of this abnormality, the diabetic patient is unable 
to properly utilize sugar (glucose) and excess amounts of it build up in 
the blood and spill over into the urine. It is an extremely complex 
disorder which is now known to encompass alterations in fat and protein 
metabolism as well as sugar metabolism, 

For many years researchers have been attempting to clarify the 
exact manner in which insulin acts, as well as determine the specific 
tissues upon which it acts. Within the past decade it has become 
increasingly certain that one of insulin's most important functions is 
to stimulate the transport of glucose across cell membranes, so that 
energy- containing glucose can enter the cell from the outside. 

Recent studies by Institute grantees at Harvard Medical School 
suggest that fat tissue, far from being merely an inert storage side of 
body fats, may be an important site of insulin action. Fat tissue taken 



lie:' 



- 10 - 

from rats was found to be extremely sensitive to small amounts of the 
hormone. The addition of insulin made the rate of sugar metabolism 
increase six times in the tissue , apparently by making more extracellular 
glucose available for intracellular metabolism. 

It has also been demonstrated that insulin exerts a clear cut 
effect on protein and fat metabolism which is exclusive of its effects 
on glucose transport. An Institute grantee at the University of Chicago 
has shown that insulin can influence protein synthesis within the cell 
by a mechanism which is independent of the passage of either amino acids 
or glucose into the cell. 

There is still much to be learned about basic mechanisms that are 
operating in this common metabolic disease. More research on the spatial 
configuration and function of insulin is needed > and because of many inter- 
relationships, the biochemistry and metabolism of other regulators-- 
especially the hormones of the pituitary and adrenal glands — must be 
further investigated. 

The Cli nic al Problem. Though the discovery of insulin still ranks 
as the most important medical advance in diabetes, the recent widespread 
use of the new oral antidiabetic drugs has brought about major changes 
in the treatment of thousands of diabetics, freeing many of them from 
daily injections of insulin. It is estimated that nearly a third of all 
known diabetics are now using these drugs which can lower the level of 
blood sugar. 

In June 195? after widespread clinical tests, the first of these 
oral hypoglycemic agents- -tolbutamide (Orinase) -became available to 



l.:.- Li I 



- 11 - 

physicians, and thousands of diabetic patients found new freedom from 
the discomfort and inconvenience of regular insulin injections. 
Unfortunately, tolbutamide was not effective in all cases, particularly 
those with severe diabetes and the juvenile or "brittle' 1 type of diabetes. 

The second clinically-tested drug of this type appeared on the 
market in October 1958. This was chlorpropamide (Diabinese) which is 
slightly more potent and is excreted less rapidly than tolbutamide. These 
two drugs were followed by two others, phenformin (DBI) and metahexamide. 
The use of the latter one has now been discontinued because of its high 
incidence of undesirable side effects. 

Although the oral drugs possess one of insulin's major character 
istics, the ability to lower blood sugar, they are not identical in 
action to insulin, as it is usually administered. The most widely held 
theory is that the drugs stimulate the beta cells of the pancreas to 
release the natural store of insulin. But the complexity of the problem 
is indicated by the fact that the drugs seem to have other actions as 
well, such as the inhibition of the enzyme insulinase which naturally 
destroys insulin. 

One of the most exciting possibilities for the new oral drugs lies 
in the field of diabetes prevention. 

It has been reported to the Committee in previous years that a 
great deal has been accomplished recently in the diagnosis of early 
diabetes or "pre-diabetes" and in predicting, for certain population groups 
and even for individuals the above normal likelihood of developing the 



- 12 - 
disease. Women who have given birth to extremely heavy babies and 
children whose parents are both diabetic are almost certain to develop 
diabetes. Persons without the usual symptoms of frank diabetes but with 
a somewhat abnormal glucose tolerance curve have been shown to have an 
eight times normal probability of developing the full-blown disease. 
Brothers and sisters of diabetics apparently particularly those who show 
abnormal glucose tolerance by a special test (the so-called ''cortisone 
test' 1 ) are more likely to become diabetic than the average. These dis- 
coveries make it possible to define and study individuals and population 
groups who might be termed ''diabetes susceptible." 

Using a small group of such individuals, grantees at the University 
of Michigan have tested the glucose tolerance curves before and after 
long-sustained treatment with an oral drug and have demonstrated some 
improvement in these curves. It is as yet much too early to determine 
the precise significance of these results but it makes imperative longer 
term and more thorough observation of the possible effect of the oral 
drugs on the development of diabetes in susceptible individuals. 

"/ith such studies as these there has been an acceleration of 
interest in diabetes and in diabetes research. This is a tangible and 
certain result of the adventitious discovery of the effect of the new 
oral drugs on blood sugar level. 

BASIC RESEARCH - METABOLISM 

Nobel Prize "./inning /fork on the Nucleic Acids . Cne of the most 
outstanding achievements in basic research during our first ten years has 



•l«ffl? 



C&&1- 



- 13 - 

been the enzymatic synthesis of the nucleic acids, the chemical substances 
inside the cell that are believed to control hereditary characteristics. 
I am happy to report that this year a former chief of one of the Institute's 
research laboratories, Dr. Arthur Kornberg, who is no\^ at Stanford University 
and a grantee of ours, Dr. Severo Ochoa of New York University, received 
the 1959 Nobel Prize in Medicine for their discoveries of the mechanixm 
for the biological synthesis of ribonucleic acids (RNA) and deoxyri- 
bonucleic acids (DNA) . 

These two acids, DNA and RNA, are found in the nucleus of all 
cells and are believed to be the information centers within the cell. 
Depending upon the exact molecular structure of its nucleic acids, the 
cell performs various functions, and when it divides to form two cells 
seme of the original nucleic acids go into the new cell. This trans- 
ported nucleic acid material then orders the new cell to develop and 
function in the same manner as its parent. 

Since the human body contains many different types of cells, each 
type performing different functions, the molecules of DNA and RNA in 
these cells must also be different and thus provide for the differentiation 
of cells into organs and then into whole plants and animals. The nucleic 
acids also control the development of species and individual character- 
istics, and thus provide for hereditary continuity. Defects in these 
nucleic acids, when they are transmitted from parent to child, are believed 
to be the cause of many hereditary or familial diseases „ 



- H - 

Because of their great importance, the Institute has emphasized 
basic studj.es of the nucleic acids for the past several years, and the 
Committee may recall my mention of this work in past reports. In 1957 
we reported the first enzymatic synthesis of the nucleic acids by 
Drs, Kornberg and Ochoaj ranking it as an outstanding achievement of that 
year. Last year, we reported that although these studies cannot be 
related to any given disease in man, "nevertheless, it can be stated 
with some assurance that the information derived from these studies will 
affect profoundly the whole future course of biological and categorical 
research." 

Ws are most happy that the Nobel Prize Committee has chosen to 
honor Dr. Kornberg and Dr. Ochoa for their very important studies in 
the nucleic acid field c 

New Analgesic Marketed . Last year I reported to you that scientists 
at the Institute had developed a new and potent synthetic pain-killing 
drug that appeared to be superior to any natural or synthetic compound 
then available, This year I am happy to add that extensive clinical 
testing of the drug in more than 3,0^0 patients has confirmed our 
expectations about the drug's usefulness and safety, and six pharmaceutical 
companies have now been licensed to produce it in this country. 

The new analgesic, which we identified as NIH 7519, was developed 
by our section on analgesics and is the result of a program of basic 
research in chemistry that began 30 years ago. The aim of this program 
has been to produce a synthetic analgesic drug having a powerful 



- 15 - 

pain-killing action while at the same time being less addicting than 
morphine. NIH 7519 has several important characteristics. It is approx 
imately ten times more potent an analgesic than morphine, it is effective 
in many cases of extreme pain that are not helped by morphine, and it is 
comparatively free from such undesirable side effects as nausea, vomiting 
and respiratory depression. Unlike morphine, the new analgesic can be 
given orally , although its tendency to cause gastrointestinal disturbance 
may limit its usefulness in this manner. Since it is a synthetic product 
it frees the United States from dependency on the opium sources of the 
world. 

It should be emphasized that this drug is definitely habit-forming. 
To be sure, it appears to be fulfilling its early promise in clinical 
trials, in producing physical dependence somewhat more slowly and less 
intensely than is the case with morphine. In considering its use ; however, 
it must be kept in mind that it is addictive and must and will be controlled 
under the narcotic laws. For the reasons stated earlier, it is nevertheless 
an extremely useful and valuable drug. 

The patent rights on the chemical process for synthesizing NIH 7519 
have now been placed in the public domain and one of the six companies 
licensed to produce it, Smith Kline and French Laboratories; at the first 
of this year made it available to the medical profession under the trade 
name Prinadol. Smith Kline and French Laboratories participated in the 
development of the drug by providing experimental quantities of it for 
clinical testing. 



16 - 

I mproved Treatment for Burn Cases . No review of our first ten 
years of progress at the Institute should fail to mention the very 
impressive work that has been done by a group of our scientists studying 
burn shock and its treatment. The basic laboratory work, which began 
at the Institute in 1942. has been extended over the years to include a 
large-scale clinical study that promises to provide a more effective 
therapy for severely burned patients not only in the prevention of death 
from shock but also in successfully combatting later complications. 

Burn shock usually develops three to five hours following injury 
and accounts for a high proportion of the early deaths among victims of 
burns covering 10 percent or more of the body area. The administration 
of blood or plasma can often prevent or overcome this condition; but in 
many areas of the world there are insufficient quantities of stored 
blood to fill such needs. Major disasters in our own country could 
seriously tax our supply of blood and plasma for emergency treatment. 

Searching for a simpler treatment, the Institute scientists found 
that in mice suffering from burn shock, the oral administration of a 
solution of salt and soda was effective in preventing shock. The salt 
and soda solution was then tested in human burn patients and found to 
greatly reduce the number of deaths from shock that followed severe burns 
This form of treatment would be of inestimable value in the event of a 
large-scale catastrophe where intravenous therapy v/ould be impractical 
and adequate supplies of blood or plasma probably would not be available. 



17 - 

The study then expanded when the clinicians treating the burn 
victims noticed that many of them would appear to recover from the shock 
period immediately following the burn only to succumb to a lethal 
infection. Blood cultures showed that the infection was caused by an 
organism called Pseudomonas, which was resistant to common antibiotics. 
The problem was then brought back to the laboratory where attempts were 
made to infect experimental animals with the Pseudomonas for research 
purposes. These attempts failed until the scientists administered 
cortisone to the animals to simulate the stress of burning. Animals 
treated in this manner could then be infected with the organism and the 
search began for a suitable treatment. 

The first effective agent found for combatting the infection in 
experimental animals was gamma globulin, the blood fraction that contains 
antibodies. Preliminary trials suggested that this might be a valuable 
therapeutic agent in humans as well. A form of treatment developed later 
is the use of a specific antiserum to the Pseudomonas organisms. Pre- 
liminary observations indicate that this may be even more effective 
than gamma globulin. 

This research achievement points up the interdependency of basic 
laboratory work on the one hand and clinical investigations on the other, 
and illustrates the benefits that accrue from such a dual approach. 

FISCAL YEAR I960 

Due to the support of this Committee and the generous increases in 
the National Institute of Arthritis and Metabolic Diseases appropriation 



- 1€ - 
voted by the Congress , we have been able to strengthen very greatly the 
research and training programs in all of our areas of responsibility. 
In particular, we have greatly intensified our efforts in cystic fibrosis 
and in gastroenterology and have initiated a program in civilian nutrition 
surveys. 

CYSTIC F IBROSIS 

A Vigorous New Effo rt. An increasing proportion of the efforts 
of this Institute is being exerted in research on the extremely important, 
relatively new disease, cystic fibrosis. Recognized as a separate disorder 
only 20 years ago, cystic fibrosis is a hereditary disease of children 
and adolescents in which there is a generalized malfunctioning of mucus, 
sweat and related glands, leading to recurring pneumonias undernutrition 
and difficulty in withstanding the stressing effects of heat. The 
significance of the expanding effort in cystic fibrosis research becomes 
apparent when one realizes that this disease is responsible in the pediatric 
age group for the majority of patients with chronic lung infections, nearly 
all cases of pancreatic insufficiency and for about one-third of the 
children with cirrhosis of the liver. 

The Institute at Bethesda has taken the step of acquiring one of 
the outstanding investigators in this field ; Dr. Paul A. di Sant'Agnese 
of Columbia University. This scientist, who is also a qualified pediatric 
specialist, developed the "sweat test" which has become the generally 
accepted method of diagnosis for cystic fibrosis and has enabled many 
cases to be detected which would otherwise have gone unrecognized. His 



IS 

finding that patients with this disease excrete an abnormally high content 
of salt in their sweat is the basis for this simple , reliable and very 
important diagnostic test. In collaboration with biochemists he has 
helped to uncover the chemical abnormality of mucus composition in patients 
which seems to account for its excessive viscosity and reasonably explains 
the pulmonary pancreatic and hepatic symptoms of cystic fibrosis. Much 
more remains to be done, however, in the biochemical and physico-chemical 
characterization of the abnormal mucus before a fully effective means is 
likely to be found for dealing with it therapeutically. Dr. di Sant'Agnese 
will direct the efforts to solve this fundamental problem by chemical 
isolation and fractionation of the mucoids in bronchial secretions, in 
duodenal juice and in saliva and by testing the action on these secretions 
of varying concentrations of electrolytes, drugs and enzymes. Clinical 
studies will also be pursued to characterize more precisely the abnormalities 
in sweat electrolyte secretion in patients with various degrees of severity 
of the disease; by measuring the behaviour of sweat salts in these patients 
under various hormonal and dietary stimuli it is anticipated that much 
more will be learned about the genetically controlled but as yet unknown 
metabolic or enzymatic defect responsible for the disease. 

Since the involvement of the lungs with chronic, recurring infections 
dominates the clinical picture in the patient - the severity of this 
involvement determines his fate - therapeutic study of this aspect of 
the disease is considered most important. Investigators of the National 
Institute of Allergy and Infectious Diseases are carrying on studies of 
this aspect of the disease. 



- 20 - 

Support of research in cystic fibrosis through research and 
training grants is also being steadily extended. Currently 38 investiga- 
tive teams are being aided by the extramural programs of this Institute, 
approximately double the number supported in the last fiscal year. 

Progress made to date in research in cystic fibrosis has extended 
the life span of patients through improved antibiotic agents and has 
revealed increased numbers of patients through formulation of a specific 
diagnostic test. These developments have served to outline the magnitude 
and scope of the problem. The phase now being entered — with vigor — is 
one of determining the underlying defect and resulting mechanism of disease 
in the patient. Accomplishments during this phase should have profound 
effects on the health of cystic fibrosis patients. 

GASTROENTEROLOGY 

Subst antial Progress in a New Field. Research in gastroenterology 
is just beginning to feel the impact of the Institute's expanded program 
of support, but substantial contributions have already been made in this 
long-neglected field. More and more investigators are becoming interested 
in the diseases of the digestive system (peptic ulcer, ulcerative colitis, 
ileitis and others) and new research techniques have been developed. At 
the present time the Institute is supporting 227 active research grants 
in this area and 39 active training grants. 

At our own facilities in Bethesda we have established the nucleus 
of a new gastroenterological unit and have begun intensive studies of the 
diseases which are grouped under the term "malabsorption syndrome." 



- 21 - 

These diseases are ones in which the absorptive capacity of the small 
intestine has been affected. One of the primary aims of the new unit is 
to apply our new knowledge of biochemistry to the study of the digestive 
organs, investigating the metabolic processes that transpire in the cells 
lining the stomach, intestines and gall bladder so that these processes 
can be related to physiological activity. We are hoping to pinpoint any 
biochemical abnormalities that may be present in these diseases and to 
determine what effects these abnormalities may be having on the function 
of the digestive organs. 

Studies are also being done on the hereditary diseases of the 
gastrointestinal tract, some of which resulted in impaired digestion 
through interference with the function of the liver. Institute scientists 
are attempting to detect hitherto unsuspected biochemical lesions that 
may be genetically controlled and that may be causing some of these 
familial diseases. 

During the past year Institute- supported research has produced a 
growing number of substantial contributions, some of which are readily 
applicable to the treatment of the diseases themselves and others which 
provide more fundamental knowledge about organ function and biochemistry. 
Grantees at the University of Chicago have developed a method for producing 
a condition in animals that resembles ulcerative colitis in humans. The 
experimental colitis is produced by an immunological technique and lends 
some support to the belief that ulcerative colitis may involve some type 
of antigen-antibody reaction, although the evidence is still not conclusive. 



"o.:<- 



- 22 - 

Physicians at the University of California School of Medicine have 
developed an effective treatment for ammonia intoxication, a condition 
that occurs when the liver becomes damaged by disease and can no longer 
prevent ammonia from accumulating in the blood. They found that injections 
of the amino acid arginine would bring about a prompt reduction in blood 
ammonia levels, thereby preventing the serious neurological damage that 
would otherwise occur. 

CIVILIAN NUTRITION SURVEYS 

For the past several years we have participated with the Department 
of Defense, the State Department, the Department of Agriculture, the 
Atomic Energy Commission and the International Cooperation Administration 
in the activities of the Interdepartmental Committee on Nutrition for 
National Defense. Under this sponsorship, and at the invitation of the 
countries involved, studies have been made of nutritional conditions in 
Iran, Pakistan, Korea, the Philippines, Turkey, Libya, Spain, Ethiopia, 
Peru, Ecuador, Vietnam, Chile and Colombia, with particular attention to 
the nutritional status of their military manpox^er. Where indicated, 
corrective measures were suggested by our survey teams and initiated by 
the countries. Excellent results have been achieved. 

It has been deemed highly desirable to extend these studies to 
civilian populations and a number of requests for such surveys have 
been received by the Secretariat of the Interdepartmental Ccmmittee on 
Nutrition for National Defense from official agencies in countries in 
various parts of the world. During the present fiscal year, with funds 



- 23 - 

allocated from the I960 budget, collaborative arrangements have been 
initiated with Naval Medical Research Unit 3 for intensive clinical and 
laboratory studies of civilian populations in Egypt and in the Sudan. 
Follow-up studies and analyses of survey findings in both military and 
civilian populations are being conducted in Ethiopia, Vietnam, Chile, 
Colombia, and Ecuador. 

SUMMARY 

The first ten years of the National Institute of Arthritis and 
Metabolic Diseases have been a period of steady growth in a well-planned 
program to increase the effectiveness of national medical research. This 
program has been enhanced through the support of increased efforts by 
Institute scientists in Bethesda, by expanding support of research project 
grants to scientists throughout the country and by stimulation of the 
training of growing numbers of much better qualified investigators through 
training grants and fellowships. 

The decade has seen aolid research accomplishments in the fields 
of medicine and biology in which this Institute is so deeply interested — 
in the chronic diseases, arthritis, gout, diabetes, endocrine and 
metabolic disorders, and in the broad fundamental disciplines of bio- 
chemistry, nutrition and metabolism. More recently valuable accomplishments 
have been made during the course of the emergence and development of 
(a) studies in the genetically controlled molecular diseases, (b) germfree 
techniques for the study of nutrition and metabolism, (c) international 
research programs involving nutritional surveys of civilian populations 



Jr.- 



- 24 - 

and the investigative-epidemiologic approach to the study of many diseases 
throughout the world,, and (d) the new broad discipline of physical biology. 
Current vigorous expanding efforts are being exerted in the relatively 
young field of research, gastroenterology and in the relatively new 
disease, cystic fibrosis. 

In conclusion, Mr Chairman, the appropriation request for 1961 
is a total of $47,541,000 as compared with the appropriation of $46,862,000 
for I960. This allowance for 1961 will provide for the continuation of 
I960 program levels in all activities and will permit some increase in 
grants for research projects and minor increases in direct research 
activities, principally in cystic fibrosis, gastroenterology and nutritional 
research under germfree conditions. This request for 196l is distributed 
among program activities as follows: 
Grants : 

Research projects 132,153,000 

Research fellowships 437,000 

Training grants 6,298,000 

Direct research and supporting services 8.653.00 

Total 47,541,000 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Institute of Neurological 

Diseases and Blindness 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
'Neurology and Blindness Activities' 



Mr. Chairman and Members of the Committee: 

In reviewing the progress of research and training relating 
to the brain and central nervous system, a number of areas may be 
poinded out which hold special promise for the future. 

It is now generally recognized that neurological and sensory 
disorders constitute the primary cause of lifelong crippling in 
the United States and rank third as the cause of death. New 
statistical data emphasize again the extent to which long-term 
disability is caused by neurological disorders and stress the 
importance of the prenatal, birth, and early life period of 
development. 

In view of this vast problem, a major attack has been made 
in this area by the Institute through its Collaborative Project 
on Cerebral Palsy, Mental Retardation, and other Neurological 
and Sensory Disorders of Infancy and Childhood. The project is 
now completing its first year of study after two and a half 
years of intensive preparation. Approximately 5500 mothers and 
4200 babies were studied in the pretest phase and 3300 mothers and 
1300 babies had been studied as of October 1 in the final study 



- 2 - 
series. Early reports from the collaborating institutions hold 
many hopeful developments. 

Through important advances in our knowledge of the bio- 
chemical defects of mental deficiency, galactosemia and phenyl- 
ketonuria can both be ameliorated by special diets. Also 
a simple mass screening test for phenylketonuria has been 
developed. Through the examination of special preparations in 
tissue culture it has been found that Mongolism is attributable 
to a chromosome abnormality which probably develops at the time 
of ovulation. 

Continued research at the Bethesda Clinical Center has 
further demonstrated this year the effectiveness of surgery in 
selected cases with temporal lobe epilepsy. In experimental 
studies in neurochemistry, attempts are being made to alter the 
level of gamma- aminobutyric acid in the brain to determine the 
effect of this change on seizure activity. Investigators also 
demonstrated hyperactivity in single cells in epileptic tissue. 

The most dramatic accomplishment in the past few years in 
the field of neurosurgery has been the application of hypothermia 
to brain surgery. This procedure has proven especially valuable 
in the treatment of intracranial aneurysms. The Institute's 
cooperative aneurysm project is now evaluating and refining the 
surgical approach to this problem and much of the success of this 
study is attributable to the new surgical techniques. 

This year the Institute has laid the groundwork for a new 
epidemiological program to determine variations in the incidence 



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- 3 - 

and character of cerebrovascular diseases in different countries. 
Recent epidemiological studies relating to sclerosing disorders 
have already demonstrated a peculiar geographic distribution of 
multiple sclerosis and variations in background cosmic radiation 
at different latitudes are now being studied. Applying the 
methods of epidemiology to the study of Parkinson's disease 
promises new information on the occurrence of this crippling dis- 
order in many countries. 

During the past year, attention has been given to the 
regeneration of muscle in certain muscle disorders. Scientists 
at the Institute have successfully evaluated the anticholinesterase 
activity of drugs widely used in treating myasthenia gravis and 
are testing the effectiveness of newer, potentially useful com- 
pounds . 

During the past year there has been a continued shift of 
emphasis in the total research grants program, particularly in 
the area of sensory disorders. Three years ago the Institute had 
no research grants relating to disorders of speech; this year it 
is estimated there will be 22. There also has been a rapid 
growth in grants relating to hearing and vision — an estimated 
74 this year in disorders of hearing and 278 in disorders of 
vision. 

This rapid increase in not only quantity but quality of 
research projects is a direct result of the Institute's training 
program. During 1960, there will be approximately 190 training 



- 4 - 
programs in all neurological and sensory areas providing training 
for 9 30 trainees. Of the 930 individuals in training, a little 
less than one-third, or about 300, will complete training this 
year. 

Many scientists now believe that international studies 
could hasten the answers to unsolved neurological and sensory 
disorders. With this thought in mind, the Institute has estab- 
lished an office for international neurological research programs 
in Antwerp, Belgium, under the direction of Dr. Pearce Bailey, 
the Institute's former director. Dr. Bailey's liaison capacity 
with the World Federation of Neurology and its professional 
societies in more than forty countries will aid the Institute 
in surveying and evaluating international neurological talent 
and facilities throughout the world. 

In conclusion, Mr. Chairman, the appropriation request 
for 1961 is a total of $39,662,000 as compared with the ap- 
propriation of $41,487,000 for 1960. This allowance for 1961 
will provide for the continuation of the 1960 program levels 
in all activities and will permit some increase in grants for 
research projects. It is distributed among program activities 
as follows: 

Grants ; 

Research projects -- $24,221,000 

Research fellowships 536,000 

Training 7,339,000 



-■•Tii- Ci 



- 5 - 
D irect Operations : 

Research 6,371,000 

Review and approval of grants 934,000 

Training activities- 50,000 

Administration 211,000 



TOTAL - 39,662,000 



OPENING STATEMENT 
by 
Director, National Institute of Neurological Disease- and Blindness 

Public Healch Service 

COMMITTEE ON APPROPRIATIONS 
1961 ESTIMATE 
for 
"National Institute of Neurological Disease^ and Blindness" 



Mr. Chairman and Members of the Committee: 

It is a pleasure for me to appear before thio Committee for 
the first time as director of the National Institute of Neurological 
Diseases and Blindness. Dr. Pearce Bailey, who has been the direc- 
tor of the Institute since its founding, is now in charge of the 
Institute 1 , International Neurological Research Programs with 
offices in Antwerp, Belgium. He will serve in a liaison capacity 
with the World Federation of Neurology and as an advisor to the 
National Institutes of Health on international neurological programs, 

My scatement will review for the Committee progress in re- 
search and training relating co the brain and central nervous system 
and point out areas which hold special promise for the future. 

The brain is the most complex structural organization known 
to man. The population of cells of the brain is four times the 
human population of the earth. The integrated performance of this 
community of nerve cells is based upon functional and structural 
organization which has surpassed understanding. Although the brain 
has aroused unusual curiosity through the centuries, the magnitude 
of its complexity, inaccessibility, and inviolability has delayed 
scientific investigation. 



- 2 - 

Abouc seventy-five year^ agu there was a period oL unusual 
optimism concerning brain research. New techniques had been 
discovered which made it possible to carry out accurate micro- 
scopic studies of the brain. In addition there was a large 
unexplored field for the clinical description of disease. This 
period of extensive advance ended a„ the contributions of these 
techniques became exhausted, and there followed a period of 
inactivity and stagnation. 

Since the war, new techniques of neurophysiology and neuro- 
cheinistry, together with the use of the electron microscope and 
implanted electrodes, have again encouraged research in this long 
neglected area. Unfortunately, trained personnel were not im- 
mediately available to exploit these new opportunities. There- 
fore, when this Institute was created by Congress in 1950, its 
responsibility was not only to stimulate and conduct research 
relating co the brain and central nervous system, but to train a 
sufficient number of teachers and research scientists to supply the 
need . 

The magnitude of the neurological problem, the degree to which 
impairment is suffered before and at birth, and the extent of life- 
long disability have been underlined recently by new scatistics. The 
1956 amendments to the Old Age and Survivors Insurance broadened the 
program to include seriously disabled children aged 18 and over. It 
has been found that 94 percent of these benefits have been paid to 
persons with neurological disorders and only 6 percent to persons 
with other disorders. The figures also show that 75 percent of all 



m :.i ■ 



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- 3 - 
these disabled individuals suffered their impairment at or prior to 
birth. The amendments, of course, have L>een in effect only a short 
period of time tut there is no evidence to indicate that percentages 
will change as the number of persons in the program increases. 

For some time it has been recognized that neurological and 
sensory disorders constitute the primary cause of permanent crippling 
in the United States and rank third as the cause of death. The new 
figures emphasize again the extent to which long-term disability is 
caused by neurological disorders and stress the importance of the 
prenatal, birth, and early life period of development. 

Because researchers are convinced that conditions existing 
during the early periods of life are responsible for a large percentage 
of disabilities which may continue throughout life, a major attack has 
been made on this area by the Institute. The Collaborative Project 
on Cerebral Palsy, Mental Retardation, and other Neurological and 
Sensory Disorders of Infancy and Childhood is now completing its first 
year of study after two and a half years of intensive preparation. 
Approximately 5500 mothers and 4200 babies were studied in the pre- 
test phase and 3300 mothers and 1800 babies had been studied as of 
October 1 in the final study series. 

The early reports from the collaborating institutions hold many 
hopeful developments. For the first time, representatives from various 
disciplines across the nation are usin uniform protocols to follow 
in detail developments of pregnancy, labor, delivery, and early infancy. 
During the past year, a protocol for the examination of the placenta 



- 4 - 
was de /eloped and a manual for placental examination prepared, a 
protocol also was developed for the neurological examination of the 
newtorn infant and a training film demonstrating the technique of the 
examination completed. A procedure for collection of blood specimens 
from the pregnant woman for virus studies has been established and 
specimens from patients are being carefully filed in a newly equipped 
coldroom. As a result of these and other developments , a well-rounded 
total program is evolving. In the broadest sense, its objective is 
to evaluate those factors influencing the health of mothers and children 
throughout the nation. 

CHRONIC NEUROLOGICAL DISORDERS OF CHILDHOOD AND ADOLESCENCE 
Of all the chronic neurological disorders of childhood and 
adolescence, mental retardation and cerebral palsy affect the most 
li^es. Of the 4,200,000 children born each year, 126,000 have some 
form of mental subncrmality . Approximately one -third of the four and 
a half million mentally retarded persons in the nation are children. 
In relation to cerebral palsy, it is estimated that $216 million is 
required annually for some 360,000 patients who require special care. 

The past five years have seen important advances in our knowledge 
of the biochemical defects of mental deficiency. The fact that 
galactosemia and phenylketonuria can both be ameliorated by special 
diets has provided increasing incentives and hope in the search for 
other similar anomalies. The newly discovered Hartnup's disease and 
"maple sugar" disease may also be amenable to dietary treatment. 



- 5 - 

During the past year, a simple mass screening cet>t for 
phenylketonuria has been developed, and there is now no reason for 
this important cause of mental deficiency to go undetected and bring 
irreparable brain damage. At present, there are several simple diag- 
nostic tests available. A chemical reagent added to a wet diaper, 
the use of a diaper powder, or the use of impregnated paper, quickly 
shows an abnormal color when unusual amounts of phenylalinine are 
present. In addition, a rapid blood test is now available which will 
detect phenylketonuria as early as the fourth day of life. This is 
particularly useful in the case of a sibling of a child known to be 
affected by the disorder. 

Recent reports emphasize the effective campaign against 
kernicterus. Up until five years ago, kernicterus was responsible 
for one percent of admissions to institutions for the mentally 
defective. One institution reports that over the past three years 
not a single case of mental retardation or cerebral palsy attributa- 
ble to kernicterus has been admitted. 

One of the most important discoveries of the last five years 
relates to abnormalities of human chromosomes. It is now possible 
to observe these abnormalities through the examination of special 
preparations in tissue culture. This technical advance has demon- 
strated that Mongolism is attributable to a chromosome abnormality 
which probably develops at the time of ovulation. In addition to 
Mongolism, several other forms of mental deficiency have been found 
to be due to similar chromosomal defects. 



- o - 

Since the sex chromosomes are easily identifiable and their 
aberrations have been readily detectable, the major emphasis to 
date has been on forms of mental retardation associated with abnor- 
malities of sexual development. The new techniques, however, should 
make possible the demonstration of similar abnormalities in other 
chromosomes. It is possible that additional forms of mental retarda- 
tion will be found to be attributable to similar abnormalities. 

The importance of severe hypoglycemia in the first few days 
of life is again assuming great importance. Especially in instances 
in which mothers have experienced toxemia during pregnancy, there 
appears to be a tendency for a sudden severe fall in blood sugar 
levels in their infants. This is often associated with convulsions 
and may lead to permanent brain damage, mental deficiency, or cerebral 
palsy of the child. This condition of low blood sugar is readily con- 
trolled but requires the continuous administration of intravenous 
sugar over a rather long period of time. The recognition of the 
importance of this factor is imperative if these children are to be 
spared irreversible damage. 

A number of significant studies are being conducted to de- 
termine those factors during pregnancy which influence the welfare 
of the offspring. There is now evidence to show that variations in 
the maternal blood proteins may be correlated with the outcome of 
pregnancy. In nineteen patients in whom abnormal proteins were 
demonstrated, approximately 79 percent had an abnormal pregnancy 
outcome. It is not yet known whether the abnormal protein is 



- 7 - 
related to some intoxication, abnormality of dietary intake, or 
constitutional deface of the mother. 

The importance of diabetes as a factor in the production of 
brain damage in infancy has been ably demonstrated over the past 
five years. Most recently it has been determined thac even a mild 
degree of maternal diabetes may influence the outcome of pregnancy. 
The likelihood of such "pre-diabetes" can be detected from the 
physical characteristics of the mother and can now be affirmed by 
glucose tolerance tests during pregnancy. 

In recent years, damage to the fetus has been pinpointed to 
the time of prenatal infection. In the case of rubella, evidence 
suggests that proper use of immune globulins may prevent fetal dam- 
age. The final solution in this instance, however, depends upon 
the development of specific immunization for this disease. 

Last year it was reported that perinatal infection could be 
demonstrated promptly by placental examination and early treatment 
of the affected child. Recent placental examinations indicate that 
premature degeneration of this organ may be one of the factors 
responsible for prematurity. (Prematurity has been indicated as 
a serious factor in cerebral palsy and mental retardation.) Ab- 
normalities of certain blood chemical constituents may provide a 
clinical clue to the occurrence of such placental degeneration 
during pregnancy. 

Hydrocephalus, an excess of fluids within the skull, with 
resulting expansion of the cavities of the brain, compression of 



- 8 - 
the brain tissues, and an enlargement of the head, is another cause 
of mental deficiency and cerebral-palsy. Advances in neurosurgical 
techniques are providing new means for bvpassing points of obstruc- 
tion, permitting outflow of fluid and relieving the pressure. The most 
recent development is the perfection of a small ball valve which can 
' e placed in a tube entering one of the veins of the chest and allows 
fluid drainage into the blood stream. The ball valve prevents the 
Lack flow of blood and contamination of the spinal fluid. Another 
effective technique is the use of a long tube to connect the spinal 
fluid spaces with the abdominal cavity within which absorption of 
fluids can take place. 

EPILEPSY 

A conservative estimate regarding the total cost of epileptics 
to the nation is probably/ more than $80 million annually. New medical 
and surgical treatment now available make it possible for more than 50 
percent of the nation's million and a half epileptics to have their 
seizures controlled. The majority of these are capable of employment 
but various laws and outdated thought concerning, the disorder make 
employment opportunities difficult to find. 

Epileptic seizures result from many different conditions. Some 
of these are associated with actual brain injury and others with inter- 
ference with the brain's normal chemical reactions. This past year 
research directed toward the sur ical and medical control of epileptic 
seizures has increased at the Bethesda laboratory and through grants 
at many medical centers throughout the country. 



t. si:"! 



- 9 - 

Continued research at the Bethesda Clinical Center has further 
demonstrated this year the effectiveness of surgery in selected cases 
with temporal lobe epilepsy. These studies are concerned with the 
removal of damaged parts of the brain functioning abnormally. This 
past year, a numfear of cases coming to surgery showed a Lony deformity 
of the middle fossa which protruded through the dura into the brain. 
This deformity was not evident in the preoperative examinations and 
the cause is not clear. 

Medical studies, chief ly chemical, are being pursued to determ- 
ine the extent to which abnormal substances in the brain may be the 
cause of seizures. This research also may show how the irritant 
effects of such substances might be altered by dru^ therapy. 

Studies in neurochemistry have revealed that gamma-aminobut^ric 
acid, present in relatively large amounts in the normal brain, may 
regulate a portion of the available energy and affect levels of 
functional activity within the brain. Attempts are bein^ made to 
alter the level of this compound to determine the effect of this 
change on seizure activity. 

In another study, a compound capable of producing seizures 
was given to mice. The investigators later succeeded in finding a 
compound which corrected the abnormalities causing the seizures. 

Investigators have also demonstrated hyperactivity in single 
cells in epileptic tissue. These findings further support the theory 
that abnormally increased activity in nerve cells is the fundamental 
defect of tody action in epilepsy. 



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- 10 - 
NEUROSURGERY 

One of the most important developments of the past five years 
is the improvement of techniques for neurosurgical intervention. In 
intracranial surgery, the surgeon must operate within a very nar- 
rowly confined space and the operation is slow and tedious. Even a 
moderate amount of bleeding may seriously interfere with his ability 
to proceed. In addition, the brain is subject to rapid swelling 
which again may block the work. 

The first step forward was the development of new anesthetic 
and muscle -relaxing agents which made it possible to operate with 
very low levels of anesthesia--and often in the semi-conscious 
state. The next achievement was che development of drugs capable 
of lowering blood pressure. These contributed greatly to reducing 
hemorrhage in surgical procedures. 

The most dramatic accomplishment, however, has been the 
application of hypothermia to brain surgery. When the body is arti- 
ficially cooled, the need of the brain for oxygen is materially 
reduced, and the circulation can be interrupted for long periods of 
time--even up to fifteen minutes. This procedure has proven es- 
pecially valuable in the treatment of intracranial aneurysms --the 
sac-like dilations of the blood vessels which are subject to rupture 
and often cause death. The Institute's cooperative aneurysm pro- 
ject is now evaluating and refining the surgical approach to intra- 
cranial aneurysms. Much of the success being demonstrated in this 
study is attributable to the new surgical techniques. 



'-"! 



- 11 - 

The use of hypothermia may also prove to be of value in 
cases of head injury, Severe swelling of the brain following 
head injury leads to further damage in the post injury period. 
Animal experiments have demonstrated that moderate degrees of 
hypothermia reduce the brain's need for oxygen during these 
critical periods * In addition, hypothermia may reduce the leak- 
age of fluid from the blood vessels and thus keep down pressure* 

An important new development in this area is a technique 
through which the blood for the brain may be coded without the 
necessity of cooling the entire body. In this way the brain may 
be relieved of its need for oxygen, yet the rest of the body may 
be maintained in its normal state. 

CEREBROVASCULAR DISEASES 

The cost to the country in lost productivity and for the 
care of more than one million Americans crippled by cerebrovas- 
cular diseases is vast. Approximately 40,000 of the more than 
175,000 deaths each year from stroke and related ailments are 
in the working age group from 25 to 64 years. 

During the past two years, data have been accumulating 
in the two large cooperative projects concerned with preven- 
tion of cerebrovascular diseases. On the study of aneurysms, 
the reports are still not final. The initial results of the 
anticoagulant study have revealed that the use of anticoagu- 
lants does not produce a dramatic change in over-all mortal- 
ity. Statistical analysis is not yet sufficiently complete to 



' '. : .1 



- 12 - 
determine whether moderate improvement may or may not be accom- 
plished by this iorm of therapy. This study, however, is pro- 
viding information on certain benefits to be derived from this 
therapy, its limitations, the types of cases in which therapy is 
desirable, and the complications to be avoided. 

Anticoagulants have been found effective in the treatment of 
vertigo due either to impending thrombosis of the posterior inferior 
cerebellar artery or to recurrent basilar insufficiency. Their use, 
however, has been found difficult and sometimes hazardous and in- 
dicates that long-term anticoagulant therapy should be used for 
vertigo only if a good response to early treatment is obtained. 

This year the Institute has launched a new epidemiological 
program to determine variations in the incidence and character of 
cerebrovascular disease in different countries. This study en- 
visions comparison of changes observed in postmortem examination 
of the brain in patients from many countries under varying 
geographical and ethnic conditions. 

SCLEROSING DISORDERS 

One of the major American neurological problems deals with 
the prolonged disability of patients with multiple sclerosis and 
related demyelinating disorders. Voluntary health agencies in this 
field estimate that there are 250,000 patients with multiple 
sclerosis and pernaps another 250,000 with related disorders. 

This year the publication of the reports of the conference 
dealing with "The Biology of Myelin" represents a milestone in 



- 13 - 
development of our knowledge in this area. Kyelin--the protective 
sheath which surrounds each of the axones--is one of the essential 
building materials of the central nervous system. Destruction of 
myelin is a key feature of multiple sclerosis and other dernyelinatino 
disorders, and the rapid development of our knowledge of the chemical 
and physical processes underlying its production is important to the 
further understanding of these destructi/e processes. 

The most important discovery in the biosynthesis of lipids 
(fats) since the discovery of the mechanism of the formation of sphin- 
gosine has been the finding that long-chain fatty acids are built by 
a condensation of 3-carbon fragments, called malonyl coenzyme A. 
Before carbon atoms from carbohydrates or proteins can become fats, 
they must pass through this newly discovered intermediate stage. 

Closely connected with the study of the formation of myelin 
is the evaluation of "allergic encephalomyelitis" --the inflammatory 
process through which the myelin is destroyed in certain allergic 
conditions which have at least superficial resemblances to multiple 
sclerosis. The method of production of this disease in animals has 
now been well established, and this year brought further clarifica- 
tion of the specific chemical fraction responsible for producing the 
destructive reaction. 

Important new investigations now su-gest that by proper 
treatment with desensitizing fractions of nervous tissue, it may 



- 14 - 

be possible to modify the allergic reaction in the sensitized 
individual and thus prevent the recurrent destructive episodes 
which characterize the allergic encephalomyelitis state. 

It is still uncertain what initial process may trigger 
the sensitization which then leads to brain destruction in 
conditions such as multiple sclerosis. A causative agent for 
multiple sclerosis has still not been discovered, but increas- 
ingly the finger points toward the possibility of some as yet 
undetermined type of virus reaction^. Similarity of multiple 
sclerosis to certain virus diseases of animals is under 
investigation, 

The important clue represented by the peculiar geograph- 
ical distribution of multiple sclerosis continues to be investi- 
gated. Our most recent epidemiological investigations demon- 
strate, for example, that multiple sclerosis is over twice as 
common in the colder climate of Halifax, Canada, as it is in 
Charleston, South Carolina. This is not a racial factor but 
apparently depends upon some geographic or climatic difference. 
Once the disease is established, it has not been shown that 
removal to a different climate influences its course. 

There is some possibility that the differential incidence 
associated with climate may be secondary to variations in back- 
ground cosmic radiation found at different latitudes. This 
question is now under study. 

Studies conducted jointly by this Institute and the 
Veterans Administration are providing information regarding the 



- 15 - 
life history of multiple sclerosis in individuals diagnosed as 
having this disease during the war years. It has been demon- 
strated that retrobulbar neuritis-- formerly thought to represent 
a precursor of multiple sclerosis--eventuates in the full disease 
in a relatively small percentage of cases, probably under 20 
percent. 

The Institute cooperated with the Danish Multiple Sclerosis 
Society and the World Federation of Neurology's Commission on 
Biometry and Genetics, to sponsor a Geomedical Conference on 
Multiple Sclerosis in Copenhagen last June. The principal 
theme of the conference concerned studies of the frequency of 
multiple sclerosis in various geographic areas of the world and 
the evaluation of current epidemiological techniques used in 
geographic neurology. 

NEUROMUSCULAR DISORDERS 
Diagnosis and treatment of the various types of diseases 
of muscle present one of the most complex neurological problems. 
Generally these disorders fall within three categories: diseases 
of the muscle itself, or muscular dystrophies, in which the 
muscle tissue seems to be diseased or destroyed; disorders af- 
fecting the muscle-exciting system and the initiation of muscle 
contraction, such as myasthenia gravis and certain familial periodic 
paralysis disorders; and inflammation of the muscle known as 
myositis. Differentiation witl.vn the categories has been difficult. 
Research during the year has resulted in advances in diagnostic 
techniques. 



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Muscle biopsy has proved to be an effective means of differ- 
entiating certain types of neuromuscular disorders. Uith this 
technique, a more exact diagnosis and earlier prognosis may be made. 
In the case of some of these disorders, treatment may prove bene- 
ficial if started early in the development of the disorder. Another 
technique of great value in the diagnosis of muscle diseases is 
electromyography. 

During the past year attention has been given to the re- 
generation of muscle in various neurogenic and primary muscle dis- 
orders. An inclusive study of the primary pathology of peroneal 
muscular atrophy has been concluded and the final studies of the 
various inter-related factors in cationic paralysis have also been 
concluded. 

Scientists at the Institute have successfully evaluated the 
anticholinesterase activity of drugs widely used in treating myas- 
thenia gravis. By correlating this activity with the drugs' clinical 
usefulness, scientists are establishing a basis for testing newer, 
potentially useful compounds. 

In addition, a new series of anticholinesterase drugs de- 
rived from plants of the Amaryllis family may offer advantages in 
the treatment of myasthenia gravis. Tests show that the antichol- 
inesterase activity of these compounds ranges from equal to somex^hat 
greater than drugs now in use to treat the disorder. However, ex- 
tensive clinical trials will be necessary before the drugs are 
admitted to general use. 



- 17 - 

INVOLUNTARY MOVEMENTS - -TREMORS AND SPASMS 

While progress continues in surgical relief for involuntary 
movements, the search for preventives and for medical control has 
intensified lecause surgery apparently will never be a fully satisfy- 
ing control method. In Parkinson's disease alone, an estimated 
million and a half persons are afflicted. 

Surgical methods for the relief of involuntary movements have 
. een developed and refined during the last five years. Originally, 
these were developed primarily for the relief of rigidity and tremor 
in Parkinsonism . More recently, other bizarre forms of involuntary 
movement and spasm have proven capable of relief by surgical measures, 
Recently, injections of dru 6 s in precise areas of the brain and 
surgical destruction of specific areas of the brain have been in- 
vesti ated. The chemical studies are providing important information 
re^ardin^ the methods through which areas of the Lrain controlling 
movement may be activated b> chemical and mechanical means. 

Neurochemists are participating in a two-pronged attack 
on Parkinson's disease. More information on the brain centers 
involved in tremor and rigidity, and detailed testin.j of possi- 
ble medicines will help progress toward control. The discovery 
that certain tranquilizing dru fo s produce Parkinsonism lends 
added impetus to this approach. 

The international application of the methods of epidem- 
iology to the study of Parkinson's disease promises new informa- 
tion on the occurrence of this crippling ailment in many countries. 



- 13 - 

ENCEPHALITIS 

The outbreak of encephalitis in New Jersey this past 
summer highlighted again the seriousness of this disease with 
its high mortality rate and the large percentage of permanent 
brain damage which follows the disorder. Many conditions cause 
encephalitis or brain fever, and it is often difficult to de- 
termine whether the cause is virus infection, allergic reaction, 
or toxic and deficiency states. 

This year more than fifty scientists from fourteen countries 
met in Antwerp, Belgium, to discuss the neuropathology and patho- 
physiology of the various encephalitides occurring around the 
world. The conferees classified and defined the known types of 
encephalitides so that a common language may be provided for the 
exchange of information among researchers throughout the world. 

PUERTO RICAN PROJECT 
This year has seen the continuing favorable development of 
the primate colony in Puerto Rico. There are now more than 260 
healthy monkeys in the free ranging colony on Cayo Santiago. 
Their physical and mental development in the free state is under 
examination. In addition, the caged colony at the University of 
Puerto Rico now has almost 100 breeding females. During the past 
year these animals have contributed strikingly to our scientific 
knowledge. Specifically, it has been possible to reproduce in 
monkeys the complete picture of cerebral palsy v;ith striking re- 
semblance to the human disorder. The mechanisms and nature of 



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- 19 - 

; ;h\3 disability are now under further investigation. 

This past summer, in collaboration with European investiga- 
tors, epoch-making investigations of the oxygenation of the unborn 
monkey were conducted. For the first time, accurate records of the 
oxygen supply of the fetus were obtained, and these will have wide 
implications for antenatal causes of fetal suffocation in the 
human . 

RADIATION EFFECTS ON CENTRAL NERVOUS SYSTEM 
Aware of the desirability of developing new knowledge regard- 
ing the possible effects on the nervous system of long-continued, 
low-level radiation, the Institute initiated a new research program 
in this area. Although a number of studies have been completed 
which demonstrate the effects of a single large dose, there are 
wide differences of opinion regarding the effect of long-continued 
dosage on the nervous system. It has been demonstrated that even 
moderate radiation dosages have some effect on the nervous system, 
as indicated by alterations in tolerance to anesthesia, as well as 
over-all effects on longevity. It is now necessary to determine 
the effects of long-continued, low-level irradiation. 

AGING 
The Institute has placed an emphasis on the two extremes of 
age -- the tragic neurological and sensory disabilities of children 
which often continue as serious lifelong disorders, and the crip- 
pling conditions of old age which shorten the satisfying period of 






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- 20 - 

usefulness. As the life span has lengthened, such disorders as 
Parkinson's disease, cataracts, glaucoma, and cerebrovascular 
diseases, mostly associated with later life, have loomed as larger 
problems. Special attention, therefore, is being given to research 
directly related to these disorders and to research on the aging 
process of the central and peripheral nervous systems. 

Institute and grant-supported investigators are currently 
pursuing two major avenues: one assumes that the aging process 
may be a natural pattern of growth; the other, that aging is not 
inevitable or normal but rather that it results from repeated in- 
juries or toxic reactions operating over a life span. Therefore, 
a number of studies have been developed to determine alterations 
in the physical and chemical structures of the tissues with aging. 
Colonies of aging animals are being maintained in various centers 
for research on such alterations in the aging process. 

The proceedings of the symposium on aging, reported pre- 
viously, have now been published and are proving to be a stim- 
ulant for researchers in this field. 

DISORDERS OF VISION 
Research relating to the major blinding disorders, such as 
cataract, glaucoma, uveitis, retinopathy, and ocular tumors, con- 
tinued to progress this year. An estimated 70 million people in 
the United States have some form of eye defect. Of these, a 
third of a million are considered legally blind, including 
35,000 children and 225,000 adults over 50 years of age. It has 



V'Jji 



- 21 - 
been estimated that blindness costs this country over $500 million 
a year. We now know that some 50 percent of all blindness can be 
prevented, and this figure is increasing constantly as a result of 
research and training efforts in this field. 

An important cause of blindness in the older age groups is 
glaucoma--a condition associated with increased pressure of fluids 
within the eye a In most cases, this pressure is caused by an un- 
known obstruction of the normal outflow of aqueous humor from the 
eye. Thousands are blinded each year because glaucoma was not 
detected in time, and, more important, there are an estimated one 
million persons with undetected glaucoma. 

For these reasons, the Institute, in cooperation with the 
Bureau of State Services, has launched a 5-year cooperative study 
to evaluate techniques currently used to detect and identify 
glaucoma. The four participating institutions will concentrate 
their efforts on developing methods of diagnosing glaucoma earlier 
than present methods permit. 

Related basic research is underway to measure the outflow 
and formation of aqueous fluids in the normal and diseased eye, as 
well as the factors which regulate the fluid pressure. The effects 
of various drugs such as acetazolamide on relieving intra-ocular 
pressure are also being investigated. 

This year, Institute grantees have reported valuable new 
techniques for diagnosing certain types of glaucoma. The results 
of an 8-year survey show that the technique of tonography, where 



«5.r 



- 22 - 
intra-ocular pressure is measured, offers criteria for early diag- 
nosis of primary glaucoma. Another grantee study indicates that 
certain tissues in the eye are damaged early in the course of 
glaucoma and that therapy should decrease pressure to a point 
where these tissues will escape damage. 

Detachment of the retina is another cause of blindness. Years 
ago, scientists found that this separation could be arrested if a 
small surgical scar was produced, causing inflammation and adhesion 
of the retina to the underlying choroid. A new method of sealing 
these breaks has been devised where an intense light is focused on 
the retinal surface. The scarring thus produced, without surgical 
intervention, may seal the retina to the choroid and prevent fur- 
ther detachment. 

An outstanding development in the cataract program is the 
demonstration of minute changes in the structures and fibers of 
the cataractous lens. Using the electron microscope, investiga- 
tors have found that cytoplasmic changes also occur early after 
irradiation, which may lead to cataract formation. 

A new project was initiated this year to evaluate the ef- 
fects of alphachymotrypsin, an enzyme which facilitates the surg- 
ical removal of cataracts. A result of this study has demonstra- 
ted the process of cell division in the corneal epithelium. A 
new and rapid method for producing experimental cataracts has also 
been devised by Institute scientists. 

Although little is generally known about treatments for 



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- 23 - 
uveitis, investigators have found that some of the resulting inf lam- 
nation responds well to steroid therapy. Where uveitis is caused 
by toxoplasmosis, therapy has been effective in 50 percent of 
treated cases. More of these favorably reacting cases were under 
age 20 with an acute or subacute course. Older chronic cases 
reacted less favorably. 

DISORDERS OF HEARING AND SPEECH 

Hearing impairment is a major cause of difficulty in speak- 
ing and understanding language and it is estimated that there are 
some 15 million Americans with hearing defects. Approximately 
415 million of these are seriously handicapped by deafness, and 
about 760,000 are totally deaf. In addition, from two to five 
percent of American children between the ages of 5 and 20 have 
speech disorders which interfere with normal development. Because 
so many are afflicted with speech and hearing disorders, and so 
few investigators have been available, a major program of both 
training and research has been directed to this area. 

Progress was made this past year in basic research studies 
of the nerve pathway by which the brain itself controls the sensi- 
tivity of hearing. The arrangement of the nerve terminals and 
manner of distribution within the ear have bean determined, and 
illustrated by a plastic three-dimensional m~del which shows the 
course and distribution of cochlear nerve fibers. Other con- 
nections of the cochlear neucleus have been studied and two new 
bundles of effectant nerve fibers have been identified. These 



- 24 - 
studies are increasing, our understanding of the brain's control over 
the hearing process. 

For the first time, investigators have described a mechan- 
ism whereby nerve impulses in individual auditory nerve fibers 
are initiated by receptor organs. Experiments with toatlly-deaf 
"waltzing guinea pigs were instrumental in determining the source 
of electrical potential within the cochlea. 

Grant-supported research in this field covered a wide range 
of research projects. One of these concerns otosclerosis, an 
important cause of deafness, especially in the older age group. 
In this disorder, the small bones of the inner ear, through which 
sounds are normally transmitted, become rigidly fixed in position 
and are no longer capable of transmission of the sound vibration. 
The first approach to this disabling condition was the "stapes 
mobilization operation." Through this procedure, the rigid bands 
holding the bones were r&leased. The bones were then "mobilized," 
and in many instances considerable improvement was established. 
An unfortunate feature of this procedure lies in the fact that 
scar tissue may once again lead to the rigid fixation of these 
structures. This year a new approach to this problem has been de- 
veloped. This consists of by-passing the rigid bones with a very 
thin plastic tube. Once accurately placed, the tube serves as a 
channel for the transmission of the vibration directly to the sensi- 
tive internal ear. The new plastic materials do not produce irritation 



- 25 - 

or inflammation of the tissues, and it appears that they may serve 
as a permanent restorative for hearing in patients suffering from 
this disorder. 

During the past year, several new projects were supported in 
the field of speech disorders and related subjects. In one such 
study, investigators fabricated a larynx of tubing and were able 
to film the various movements of this larynx. They suggest that 
the shape of a thyroid muscle may determine the frequency of 
vibration of the vocal cords. 

In addition, the Institute's collaborative project includes 
correlations of hearing and speech disorders with events of pregnancy 
and labor. This program offers new opportunities in the speech and 
hearing field. 

TRAINING GRANTS 

The unusual need for trained investigators in the area of 
neurology, sensory disorders, and related disciplines has made it 
imperative for the Institute to advance its training program as 
rapidly as possible. 

The Institute's training program has been in effect for 
seven years and is now well established. During 1960, there 
will be approximately 190 training programs providing training 
for 930 trainees. Of the 930 individuals in training, a little 
less than one-third or about 300 will complete training this 
year. 



- 26 - 

Training is already well developed in clinical neurology 
with 60 programs and in ophthalmology with 35 programs. No major 
expansion is contemplated in these two areas. These programs, 
however, need to be strengthened by placing greater emphasis on 
the applicability of basic research methods to clinical problems. 
There has been a need to develop scientists with knowledge of 
basic research techniques who have the ability to bring these 
talents to bear on the problems of neurological disease. There- 
fore, most of the expansion in 1960 was in the basic science pro- 
grams which now number 49. These include 6 in neurochemistry, 8 
in neuroanatomy, 7 in neurophysiology, 8 in neuropharmacology, 
15 in neuropathology, and 5 in sensory physiology. 

Clinical otolaryngology is still behind other programs but 
has expanded frcm 23 to 29 programs in 1960. To fill a continu- 
ing need for pediatric neurologists, there are now 12 training 
programs. Also, there are now 5 programs in medical audiology. 

SPECIAL TRAINEESHIPS 
The success of future research in solving the problems of 
neurological and neuromuscular diseases, blindness, and deafness 
will depend primarily upon the competence and investigative skills 
of the basic scientists and clinicians being trained now for careers 
in research. The complexity of the problems faced demands that this 
training be specialized, diversified, and of the best quality to be 
obtained anywhere in the world. Training support must therefore be 
provided at advanced academic levels, beyond that ordinarily covered 



- 27 - 

by the Training Grant programs . Special Traineeships are proving to 
be specially valuable as a means of fostering research careers for 
those young men and woman who will form the backbone of our future 
research program. Additionally, since investigative medicine is a 
lifelong study, the Special Traineeship program is being utilized 
by mature teacher-investigators to keep abreast of advances in their 
individual fields of research interest. 

Currently 207 trainees in 26 fields are in the Special 
Traineeship program. Almost without exception, men who have com- 
pleted such traineeships move rapidly into academic positions and 
develop laboratories undertaking independent research. 

RESEARCH FELLOWSHIPS 

The purpose of the research fellowship program is to aid 
young men and women who have manifested a desire for investigative 
careers to become more expert by providing a part of the cost of 
further academic training and research experience. If progress is 
to be made in solving neurological and sensory disease problems, 
the maintenance of a continuing supply of research manpower must 
be assured. This program has proven to be an effective means of 
achieving this objective, since more than 75 percent of those re- 
ceiving training remain in research and teaching. 

It is believed that the Research Fellowship funds available 
now should be sufficient to meet the research training needs of 
those whom it may be highly desirable to support in departments 
where no training programs have been established. 



- 28 - 
INTERNATIONAL RESEARCH 

Many scientists now believe that international studies could 
hasten the answers to unsolved neurological and sensory disorders. 
They are convinced that studies regarding the nature and frequency 
of disease in relation to genetic and environmental factors in 
diverse geographic regions and populations could add much to our 
present store of scientific knowledge. With this thought in 
mind, the Institute has established an office for international 
neurological research programs in Antwerp, Belgium. 

Under the direction of Dr. Pearce Bailey, the Institute's 
former director, the program has two immediate aims. The first 
is to survey, evaluate, and report on international scientific 
talent and facilities for research and training in neurological 
disorders. The second is to study and develop methods for the 
application of this potential to the organization of promising 
collaborative projects in international geographic clinical 
pathology. 

At the present time, two specific studies are considered 
suitable for development: one relates to cerebrovascular diseases 
and the other to disorders arising during pregnancy, birth, and 
early infancy. The Institute's Advisory Council has recommended 
the allocation of funds to the World Federation of Neurology 
which has applied for a grant to develop a collaborative neuro- 
pathological study of cerebrovascular diseases. A number of 
European investigators have already expressed interest in re- 
search relating to disorders arising in the perinatal period. 



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- 29 - 
In surveying and evaluating international neurological 
talent and facilities, Dr. Bailey's liaison capacity with the 
World Federation of Neurology and its professional societies 
in more than forty countries will be helpful. 

A TECHNICAL APPROACH TO NEUROLOGICAL PROBLEMS 
A review of progress in recent years demonstrates the fre- 
quency with which major medical discoveries have stemmed from 
technological advances. Increasingly the medical scientist is 
dependent upon the skills and techniques of the industrialist 
and the technologist. The time has come when greater resources 
from those of industry should be diverted toward the solution of 
the important problems of national health. During the next year, 
this Institute proposes to launch a determined campaign to acquaint 
industry with medical problems relating to the brain and central 
nervous system. It is hoped that industrial scientists from many 
disciplines may bring new approaches to many unsolved problems. 

SUMMARY OF RESEARCH ACCOMPLISHMENTS 
The magnitude of the unsolved problems relating to neuro- 
logical disorders could easily lead to discouragement and pessi- 
mism. It is healthy, therefore, to consider the concrete achieve- 
ments of the last five or ten years, noting that each has served 
in some way to reduce the toll of misery and disability of these 
dread disorders. 

In the field of cerebral palsy, it is heartening to note 
that kernicterus has been practically eliminated. This disorder, 



- 30 - 
which formerly accounted for more than one percent of all ad- 
missions to our institutions for the mentally defective, did not 
account for a single admission to one of our largest State 
institutions over the last three years. 

In the area of mental deficiency, the dietary treatment 
of phenylketonuria, although not presenting the ideal solution 
of this tragic problem, is already saving numerous victims from 
hopeless idiocy. This is another condition which formerly ac- 
counted for about one percent of admissions to our institutions 
for the severely defective. Galactosemia and a new disorder-- 
"maple sugar" disease, also associated with abnormalities of body 
chemistry, may also be amenable to dietary treatment. 

Although not leading to direct elimination or cure, the dis- 
covery of the chromosomal causes of Mongolism represents a tremendous 
advance, and opens the way toward accurate knowledge of the causes 
of this most important form of mental deficiency. 

The last five years has seen the refinement of surgical 
methods for the relief of involuntary movement. This has been 
helpful not only for Parkinsonism but also for other bizarre forms 
of movement and spasms. 

In our campaign against blindness, retrolental fibroplasia 
has been completely eliminated. The new technique of corneal trans- 
plantation is bringing useful vision to many people whose lives 
otherwise would have been spent in darkness. Drug therapy of 
glaucoma, while not always effective, has tremendously reduced 
the toll of blindness attributable to this disease. 



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- 31 - 

There are encouraging reports of restoration of hearing in 
patients suffering from otosclerosis. This form of deafness, prev- 
alent in the older age groups, is rapidly yielding to newly devel- 
oped surgical measures of relief. 

Our techniques for the control of certain brain diseases 
have also undergone great improvement. The use of the radioactive 
tracer scanning technique for the localization of brain tumors has 
simplified the early diagnosis of tumors, and is facilitating their 
surgical removal. The development of new anesthetic agents, and 
especially of hypothermia for brain operations, has caused a sharp 
drop in the operative mortality of such conditions as cerebral 
aneurysms and brain tumors . Ruptured cerebral aneurysm has in the 
past carried with it a mortality of over 50 percent. In selected 
cases, highly successful operative intervention is now feasible. 

Training, also, has seen tremendous advances during this 
period. In 1952, there were 15 training programs in clinical 
neurology in 79 medical schools in the country. At that time there 
were only 90 residents in training and about 250 qualified neurolo- 
gists in the United States. Six states did not have a single 
board-certified neurologist. 

Today, with 85 medical schools this Institute has 60 
training programs with 285 trainees in clinical neurology. There 
are now 798 board-certified neurologists with qualified neurologists 
in every state. 

During the past year there has been a continued shift of 
emphasis in the total research grants program, particularly in 



- 32 - 

the area of sensory disorders. Three years ago the Institute had 
no research grants relating to disorders of speech. In 1959, there 
were 17, and this year it is estimated that there will be 22. The 
grants relating to hearing have also had a rapid growth with 49 in 

1958, 57 in 1959, and an estimated 74 this year. From the early 
founding of the Institute there have been research grants relating 
to disorders of vision. This area, also, has grown the last two 
years. There were 137 grants relating to vision in 1958, 200 in 

1959, and an estimated 278 in 1960. 

This rapid increase in not only quantity but quality of 
research projects is a direct result of the Institute's training 
program. It represents a strengthening of areas of research 
previously neglected. It is anticipated that these trends 
will continue in 1961. 

In conclusion, Mr. Chairman, the appropriation request for 
1961 is a total of $39,662,000 as compared with the appropriation 
of $41,487,000 for 1960. This allowance for 1961 will provide for 
the continuation of the I960 program levels in all activities and 
will permit some increase in grants for research projects. It is 
distributed among program activities as follows: 

Grants : 

Research projects-- $24,221,000 

Research fellowships-- 536,000 

Training - 7,339,000 



- 33 - 
Direct Operations : 

Research ~ 6,371,000 

Review and approval of grants 934,000 

Training activities 50,000 

Administration 211,000 



TOTAL 39,662,000 



OPENING STATEMENT 
by 
Associate Director, National Institutes of Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1961 ESTIMATE 

for 

Grants for Construction of Health Research Facilities 7 



Mr. Chairman and Members of the Committee: 

Now in its fourth year of operation, the Public Health service 
program uhich provides grants to construct and equip health research 
facilities v;as initially established as a three-year program through 
the Health Research Facilities Act of 1956 (Title VII of the Public 
Health Service Act, enacted as P.L. 335, 34th Congress). This 
Act was extended for an additional three-year period by the 35th 
Congress (P.L. 777) in August 1953. Initially, and under the 
three-year extension, the Congress authorized appropriations of up to 
$30,000,000 during each fiscal year to provide grants 'to nonfederal 
public and nonprofit institutions for constructing and equipping 
facilities for research in the sciences related to health.' Grants 
are av7arded on a matching fund basis, uith the Federal share not to 
exceed fifty percent of the costs for the research facilities 
portion of such construction. The program is administered by the 
Division of Research Grants of the National Institutes of Health. 



- 2 - 

Appropriations of $120,000,000 have been made by the Con- 
gress during the first four program years--fiscal years 1957 
through 1960. An appropriation of $25,000,000 is requested for 
1961, 

A requirement of the Research Facilities Act is that an 
Annual Report be prepared, submitted to the President, and trans- 
mitted to the Congress. The first three reports submitted in re- 
sponse to this requirement have been printed as House Documents 
21 and 324 of the 85th Congress, and House Document 73 of the 
86th Congress. The Fourth and current report is being prepared 
and will be referred to the Congress at this session of the 86th 
Congress. 

PROGRESS REPORT ON GRANTS AWARDED 

Since the inception of this program a total of 872 new, 
revised, and supplemental applications for construction grants 
have been received. These requests for assistance in the construc- 
tion of research facilities have been submitted by all types of 
institutions engaged in various phases of health related research-- 
public and private nonprofit schools of medicine, dentistry, 
osteopathy, and public health, as well as hospitals, universities, 
and other research institutions. Up to the present time, the Sur- 
geon General has awarded a total of 633 grants to 277 institutions 
in 46 States and the District of Columbia. These grants represent 
a total Federal expenditure of $118,210,963. 



- 3 - 

Seventy-two medical schools have received 199 grants 
valued at $64,782,256; 15 dental schools have been awarded 
$2,108,186 (16 grants); 5 schools of public health have received 
7 grants in the total amount of $3,016,605; 2 schools of osteo- 
pathy were awarded 2 grants, in the sum of $105,298; other schools 
with research areas of interest to the Public Health Service, such 
as those of veterinary medicine, pharmacy, chemistry and the bio- 
logical sciences have been awarded 211 grants in the total amount 
of $26,368,596; and other public and private nonprofit institu- 
tions, hospitals and independent research institutions have re- 
ceived 196 grants, valued at $21,830,022, 

Construction progress . - During 1959, 147 projects were 
completed and are in use. These facilities represent expendi- 
tures of $15,983,118 in Federal funds and total construction costs 
of more than $81 million. Some 180 additional projects currently 
are under contract, representing Public Health Service grants in 
the amount of $55,690,799, 



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